Assessment of risk for colorectal cancer

ABSTRACT

Disclosed is a method for identifying an individual who has an altered risk for developing colorectal cancer comprising detecting a single nucleotide polymorphism (SNP).

FIELD OF THE INVENTION

This invention relates to prediction of the susceptibility of an individual to colorectal cancer. Basis for the prediction lies in relating an individual's genetic makeup, as through molecular analysis, to the genetic makeup of a population of individuals.

BACKGROUND

During the course of evolution, spontaneous mutations arise in the genomes of organisms. Variations in genomic DNA sequences are created continuously at a rate of about 100 new base changes per individual (Kondrashov, 1995; Crow, 1995). These germ-line changes may produce an evolutionary advantage and be retained in the population, or they may be deleterious and ultimately eliminated. In many cases, equilibrium between multiple germline forms of a sequence is established within a population if reproductive ability of individuals containing either polymorphism is not affected. Over time, significant numbers of mutations have accumulated within the human population that may be observed to varying extents in geographically separated groups based upon the presence of common ancestors.

Colorectal cancer is the third most common cancer and the third most common cause of death from cancer for both men and women. Colorectal cancer is responsible for more deaths that are not due primarily to tobacco use than any other type of cancer and inflicts a huge financial burden. Early detection of some human tumors such as uterine cervical cancer has dramatically reduced mortality from this condition (Herzog, 2003). Early detection of colorectal cancer can reasonably be expected to prevent death from this condition by identifying patients at risk for the disease, or those with the disease in an early stage and allow life saving intervention. A validated genetic test for colorectal cancer predisposition will have clinical utility, allowing prevention of cancer mortality through targeted screening programs. There are good reasons to expect that at least some of the genetic risks of common disease is due to common variants—for example, based on evolutionary arguments, and the fact that most human genetic variation is common. Although approximately 20% of colorectal cancers have a familial component with relatives exhibiting a doubling of risk (Carstensen et al., 1996), less than 5% of colorectal cancer is explained by rare, highly penetrant genetic syndromes such as APC and HNPCC (de Leon et al., 1999). Familial colorectal cancer occurring in patterns inconsistent with classical inherited syndromes suggests that variation in genome sequence plays a major role in determining individual risk to colorectal cancer. These genetic causes appear complex due to a variety of reasons such as genetic heterogeneity, incomplete penetrance, phenocopies and variation in exposures to environmental co-factors etc. There is little insight into the genetic or environmental determinants of almost 90% of cases of human colorectal carcinoma (Lynch and de La, 2003).

Although common human genetic variation is limited compared to other species, it remains impractical to discover and test every one of the estimated 10,000,000 common genotype variants (Sachidanandam et al., 2001) as predictors of disease risk. Genotypic complexity is reduced through linkage disequilibrium that exists across long segments of the human genome with restriction in the diversity of haplotypes observed (Daly et al., 2001; Rioux et al., 2001; Liu et al., 2004). That is, single nucleotide polymorphisms found at specific locations within the human genome are inherited in conjunction with nucleotides that can be polymorphic that are physically located near by. In European genomes, allelic association between pairs of markers typically extends over 10-50k, although there is tremendous variability in the magnitude of association observed at any given distance (Clark et al., 1998; Kikuchi et al., 2003; Dunning et al., 2000; Abecasis et al., 2001). Genome-wide data (Gabriel et al., 2002; Reich et al., 2001; Dawson et al., 2002) supports the generality of this description as well as its application across populations. This confirms that measurement of single nucleotide polymotphisms at sites in tight linkage disequilibrium with adjacent genomic regions can provide information about the presence of diversity not just at sites actually measured, but also about large areas of the adjacent genome.

Numerous types of polymorphisms exist and are created when DNA sequences are either inserted or deleted from the genome. Another source of sequence variation results from the presence of repeated sequences in the genome variously termed short tandem repeats (STR), variable number of tandem repeats (VNTR), short sequence repeats (SSR) or microsatellites. These repeats commonly are comprised of 1 to 5 base pairs. Polymorphism occurs due to variation in the number of repeated sequences found at a particular locus.

The most common form of genomic variability are single nucleotide polymorphisms or SNPs. SNPs account for as much as 90% of human DNA polymorphism (Collins et al., 1998). SNPs are single base pair positions in genomic DNA at which different sequence alternatives (genotypes) exist in a population. By common definition, the least frequent allele occurs at least 1% of the time. These nucleotide substitutions may be a transition, which is the substitution of one purine by another purine or the substitution of one pyrimidine by another, or they may be transversions in which a purine is replaced by a pyrimidine or vice versa.

Typically SNPs are observed in about 1 in 1000 base pairs (Wang et al., 1998; Taillon-Miller et al., 1999). The frequency of SNPs varies with the type and location of the change. Specifically, two-thirds of the substitutions involve the C

T (G

A) type, which may occur due to 5-methylcytosine deamination reactions that occur commonly. SNPs occur at a much higher frequency in non-coding regions than they do in coding regions.

Known environmental risk factors for the development of colorectal cancer include obesity, absence of a vegetable-rich diet and a sedentary life style. Estrogen use in post menopausal women is associated with reduced individual risk for the development of colorectal cancer. The mechanism of risk reduction through the chronic administration of estrogen is unknown and a way of quantifying altered risk associated with estrogen use is not obvious. It is known that expression of the estrogen receptor beta on colorectal tumors is reduced compared to undiseased adjacent tissue. It is not known if this observation has any relevance to the reduced incidence of colorectal cancer in women taking postmenopausal estrogen, nor is it useful in predicting individual risk for the development of colorectal cancer. It is not known if single nucleotide polymorphisms within the estrogen receptor beta can modify the risk of developing colorectal cancer conferred by certain polymorphisms in other risk genes.

SUMMARY OF THE INVENTION

It has been discovered that polymorphic variations in a number of loci in human genomic DNA are associated with susceptibility to colorectal cancer. This invention thus includes methods for identifying a subject at risk of colorectal and/or determining risk of colorectal cancer in a subject, which comprise detecting the presence or absence of one or more polymorphic variations associated with colorectal cancer in a nucleic acid sample from the subject. In a specific embodiment, this invention relates to identifying an individual who is at altered risk for developing colorectal cancer based on the presence of specific genotypes defined by 85 single nucleotide polymorphism (SNPs), observed alone or in combination. Through large scale genotyping studies on 2,373 blood samples from patients with colorectal cancer and 2,296 control samples from unaffected individuals we have identified 85 polymorphic markers found in 32 genes which are found more frequently in patients with colorectal cancer than in those without this disease. These markers, or those in close linkage disequilibrium, may change the composition, function or abundance of the elements of cellular constituents resulting in a predisposition to colorectal cancer. Measuring these markers in individuals who do not ostensibly have colorectal cancer will identify those at heightened risk for the subsequent development of colorectal cancer, providing benefit for, but not limited to, individuals, insurers, care givers and employers. Genes containing colorectal cancer-associated polymorphic markers that we have identified and genes found in linkage disequilibrium with these that we have identified are valuable targets for the development of therapeutics that inhibit or augment the activity of the gene products of these genes for therapeutic use in, but not restricted to, colorectal cancer. Information obtained from the detection of SNPs associated with colorectal cancer is of great value in the treatment and prevention of this condition.

Accordingly, one aspect of the present invention provides a method for diagnosing a genetic predisposition to colorectal cancer in a subject, comprising obtaining a sample containing at least one polynucleotide from the subject and analyzing the polynucleotide to detect the genetic polymorphism wherein the presence or absence of the polymorphism is associated with an altered susceptibility to developing colorectal cancer. In one embodiment, one or more of the 85 polymorphisms found distributed among 32 genes that we have identified may be used.

Another aspect of the present invention provides an isolated nucleic acid sequence comprising at least 16 contiguous nucleotides or their complements found in the genomic sequences of the 32 genes adjacent to and including the 85 polymorphic sites the inventors have identified to be associated with colorectal cancer.

Yet another aspect of the invention provides a method for treating colorectal cancer comprising obtaining a sample of biological material containing at least one polynucleotide from the subject, analyzing the polynucleotides to detect the presence of at least one polymorphism associated with colorectal cancer and treating the subject in such a way as to counteract the effect of any such polymorphism detected.

Still another aspect of the invention provides a method for the prophylactic treatment of a subject identified with a genetic predisposition to colorectal cancer identified through the measurement of all or some of the 85 polymorphic SNP markers described in Tables 1 to 85.

Through large scale genotyping studies on 1231 blood samples from patients with colorectal cancer and 1240 control samples from unaffected individuals we have identified polymorphic sites within the estrogen receptor beta gene that act as a further risk predictor for colorectal cancer when considered along with colorectal cancer risk-predicting markers on chromosome 8q24. While polymorphic sites within the estrogen receptor beta gene, which is located at chromosome 14q23, are not predictors of colorectal cancer independent of other markers, they strongly modify the predictive power of markers at chromosome 8q24.

Accordingly, one or more of the polymorphic sites within 8q24 may be used in conjunction with one or more polymorphisms within the estrogen beta receptor locus which is found at chromosome 14q23 to more accurately predict risk of colorectal cancer as described in Table 86.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. It should be understood however, that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modification within the spirit and scope of the invention will become apparent to those skilled in the art from the following detailed description.

Tables 1 to 85 report the result of a genotyping analysis of 4,669 samples by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2,475 subjects (1,234 cases with colorectal cancer and 1,241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2,194 subjects (1,139 cases with colorectal cancer and 1,055 age matched individuals undiseased at the time of testing).

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that polymorphic variants in a number of sequences, SEQ ID NOs:1 to 1760 are associated with an altered risk of developing colorectal cancer in subjects. The present invention thus provides SNPs associated with colorectal cancer, nucleic acid molecules containing SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The colorectal cancer-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to colorectal cancer and related pathologies in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.

A large number of colorectal cancer-associated SNPs have been identified by genotyping DNA from 4,669 individuals, 2,373 of these individuals having been previously diagnosed with colorectal cancer and 2,296 being “control” or individuals thought to be free of colorectal cancer.

The present invention thus provides individual SNPs associated with colorectal cancer, genomic sequences (SEQ ID NOs:1761 to 1790) containing SNPs, and transcript sequences amino acid sequences. The invention includes methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing colorectal cancer, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as colorectal cancer, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment strategy, methods of treating a disorder associated with a variant gene/protein (i.e., therapeutic methods), and methods of using the SNPs of the present invention for human identification.

When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome correlates with an increased probability of that individual contracting colorectal cancer vis-à-vis a population not having that base at that location in the genome, that individual is said to be at “increased risk” of contracting colorectal cancer, i.e., to have an increased susceptibility. In certain cases, this effect can be a “dominant” effect in which case such increased probability exists when the base is present in one or the other or both alleles of the individual. In certain cases, the effect can be said to be “recessive”, in which case such increased probability exists only when the base is present in both alleles of the individual.

When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome decreases the probability of that individual contracting colorectal cancer vis-à-vis a population not having that base at that location in the genome, that individual is said to be at “decreased risk” of contracting colorectal cancer, i.e., to have a decreased susceptibility. Such an allele is sometimes referred to in the art as being “protective”. As with increased risk, it is also possible for a decreased risk to be characterized as dominant or recessive.

An “altered risk” means either an increased or a decreased risk.

The genetic analysis detailed below linked colorectal cancer with SNPs in the human genome. A SNP is a particular type of polymorphic site, a polymorphic site being a region in a nucleic acid sequence at which two or more alternative nucleotides are observed in a significant number of individuals from a population. A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. Each of the specific polymorphic sites found in SEQ ID NOs:1761 to 1790 is a “single nucleotide polymorphism” or a “SNP.”

Where there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a “polymorphic variant” or “nucleic acid variant.” Where two polymorphic variants exist, for example, the polymorphic variant represented in a majority of samples from a population is sometimes referred to as a “prevalent allele” and the polymorphic variant that is less prevalently represented is sometimes referred to as an “uncommon allele.” An individual who possesses two prevalent alleles or two uncommon alleles is “homozygous” with respect to the polymorphism, and an individual who possesses one prevalent allele and one uncommon allele is “heterozygous” with respect to the polymorphism. Individuals who are homozygous with respect to one allele are sometimes predisposed to a different phenotype as compared to individuals who are heterozygous or homozygous with respect to another allele.

A genotype or polymorphic variant may also be expressed in terms of a “haplotype,” which refers to the identity of two or more polymorphic variants occurring within genomic DNA on the same strand of DNA. For example, two SNPs may exist within a gene where each SNP position may include a cytosine variation or an adenine variation. Certain individuals in a population may carry an allele (heterozygous) or two alleles (homozygous) having the gene with a cytosine at each SNP position. As the two cytosines corresponding to each SNP in the gene travel together on one or both alleles in these individuals, the individuals can be characterized as having a cytosine/cytosine haplotype with respect to the two SNPs in the gene.

A “phenotype” is a trait which can be compared between individuals, such as presence or absence of a condition, for example, occurrence of colorectal cancer.

Polymorphic variants are often reported without any determination of whether the variant is represented in a significant fraction of a population. Some reported variants are sequencing errors and/or not biologically relevant. Thus, it is often not known whether a reported polymorphic variant is statistically significant or biologically relevant until the presence of the variant is detected in a population of individuals and the frequency of the variant is determined.

A polymorphic variant may be detected on either or both strands of a double-stranded nucleic acid. Also, a polymorphic variant may be located within an intron or exon of a gene or within a portion of a regulatory region such as a promoter, a 5′ untranslated region (UTR), a 3′ UTR, and in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or a polypeptide. Polymorphic variations may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.

In our genetic analysis associating colorectal cancer with the polymorphic variants set forth in the tables, samples from individuals having been diagnosed with colorectal cancer and individuals not having cancer were allelotyped and genotyped. The allele frequency for each polymorphic variant among cases and controls was determined. These allele frequencies were compared in cases and controls, or combinations. Particular SNPs were thus found to be associated with colorectal cancer when genotype and haplotype frequency differences calculated between case and control pools were established to be statistically significant.

As mentioned above, polymorphic variants can travel together. Such variants are said to be in “linkage disequilibrium” so that heritable elements e.g., alleles that have a tendency to be inherited together instead of being inherited independently by random assortment are in linkage disequilibrium. Alleles are randomly assorted or inherited independently of each other if the frequency of the two alleles together is the product of the frequencies of the two alleles individually. For example, if two alleles at different polymorphic sites are present in 50% of the chromosomes in a population, then they would be said to assort randomly if the two alleles are present together on 25% of the chromosomes in the population. A higher percentage would mean that the two alleles are linked. For example, a first polymorphic site P1 having two alleles, e.g. A and C—each appearing in 50% of the individuals in a given population, is said to be in linkage disequilibrium with a second polymorphic site P2 having two alleles e.g. G and T—each appearing in 50% of the individuals in a given population, if particular combinations of alleles are observed in individuals at a frequency greater than 25% (if the polymorphic sites are not linked, then one would expect a 50% chance of an individual having A at P1 and a 50% chance of having G at P2 thus leading to a 25% chance of having the combination of A at P1 and G at P2 together). Heritable elements that are in linkage disequilibrium are said to be “linked” or “genetically linked” to each other.

One can see that in the case of a group of SNPs that are in linkage disequilibrium with each other, knowledge of the existence of all such SNPs in a particular individual generally provides redundant information. Thus, when identifying an individual who has an altered risk for developing colorectal cancer according to this invention, it is necessary to detect only one SNP of such a group of SNPs associated with an altered risk of developing colorectal cancer.

It has been shown that each SNP in the genomic sequences identified as SEQ ID NOs:1761 to 1790 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which includes detecting the presence or absence of one or more of the SNPs described herein in a human nucleic acid sample.

Three different analyses were performed for each marker: (a) a test of trend across the 3 genotypes (Sasieni et al. 1997); (b) a dominant model where the homozygous genotype for allele “B” is combined with the prevalent heterozygote genotype; and (c) a recessive model where the homozygous genotype for allele “A” is combined with the heterozygous genotype. Using permutation analysis, the empirical p-value for the maximum of these three test statistics was calculated. Odds ratios measuring the strength of the association are also reported for the model corresponding to the largest of the three test statistics.

Pertinent results for each SNP are summarized in the tables: Chromosomal number and position-using the International Human Genome Sequencing Consortium build 35 (http://www.ncbi.nlm.nih.gov/genome/seq/) as made available by the National Center for Biotechnology Information (NCBI), National Library of Medicine, Building 38A, Bethesda, Md. 20894 U.S.A., gene marker name-using the nomenclature of the NCBI dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) and gene name-using the unigene naming convention. Under the “Case Flag” the number 1 designates Cases and the number 0 designates Controls. The identity of the base designated “A” in the analysis is indicated where 1=A (adenine), 2=C (cytosine), 3=G (guanine) and 4=T (thymidine). “B” indicates the polymorphic allele. AA, AB, BB are the counts of the number of individuals with the given genotype, by cases/controls. For dominant models, an odds ratio measuring the increase in risk associated with one or two copies of allele B is calculated. For recessive models, an odds ratio associated with exactly two copies of allele B is calculated. For the trend models, the Mantel-Haenszel odds ratio showing the increase in risk with each additional copy of allele B is calculated.

It has been discovered that each polymorphic variation in the genomic sequences identified as SEQ ID NOs:1761 to 1790 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which comprises detecting the presence or absence of one or more of the polymorphic variations described herein in a human nucleic acid sample. The polymorphic variation, SNP, are detailed in the tables.

Methods for determining whether a subject is susceptible to, i.e., at risk of colorectal cancer are provided herein. These methods include detecting the presence or absence of one or more polymorphic variations, i.e., SNPs, associated with colorectal cancer in a sample from a subject.

SNPs can be associated with a disease state in humans or in animals. The association can be direct, as in conditions where the substitution of a base results in alteration of the protein coding sequence of a gene which contributes directly to the pathophysiology of the condition. Common examples of this include diseases such as sickle cell anemia and cystic fibrosis. The association can be indirect when the SNP plays no role in the disease, but is located close to the defective gene such that there is a strong association between the presence of the SNP and the disease state. Because of the high frequency of SNPs within the genome, there is a greater probability that a SNP will be linked to a genetic locus of interest than other types of genetic markers.

Disease-associated SNPs can occur in coding and non-coding regions of the genome. When located in the coding region altered function of the ensuing protein sequence may occur. If it occurs in the regulatory region of a gene it may affect expression of the protein. If the protein is involved in protecting the body against pathological conditions this can result in disease susceptibility.

Numerous methods exist for the measurement of specific SNP genotypes. Individuals carrying mutations in one or more SNPs of the present invention may be detected at the DNA level by a variety of techniques. Nucleic acids for diagnosis may be obtained from a patient's cells, such as from blood, urine, saliva, tissue biopsy and autopsy material.

The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR prior to analysis (Saiki et al., 1986). RNA or cDNA may also be used in the same ways. As an example, PCR primers complementary to the nucleic acid of one or more SNPs of the present invention can be used to identify and analyze the presence or absence of the SNP. For example, deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to radiolabeled SNP RNA of the present invention or alternatively, radiolabeled SNP antisense DNA sequences of the present invention. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase A digestion or by differences in melting temperatures.

Sequence differences between a reference gene and genes having mutations also may be revealed by direct DNA sequencing. In addition, cloned DNA segments may be employed as probes to detect specific DNA segments. The sensitivity of such methods can be greatly enhanced by appropriate use of PCR or another amplification method. For example, a sequencing primer is used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabeled nucleotide or by automatic sequencing procedures with fluorescent-tags.

Genetic testing based on DNA sequence differences may be achieved by detection of alteration in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents. Small sequence deletions and insertions can be visualized by high resolution gel electrophoresis. DNA fragments of different sequences may be distinguished on denaturing formamide gradient gels in which the mobilities of different DNA fragments are retarded in the gel at different positions according to their specific melting or partial melting temperatures (Myers et al., 1985).

Sequence changes at specific locations also may be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method (Cotton et al., 1988).

Thus, the detection of a specific DNA sequence may be achieved by methods which include, but are not limited to, hybridization, RNase protection, chemical cleavage, direct DNA sequencing or the use of restriction enzymes, (e.g., restriction fragment length polymorphisms (“RFLP”) and Southern blotting of genomic DNA).

In addition to more conventional gel-electrophoresis and DNA sequencing, mutations also can be detected by in situ analysis.

Genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotide probes (Cronin et al., 1996; Kozal et al., 1996). For example, genetic mutations can be identified in two-dimensional arrays containing light-generated DNA probes as described in Cronin et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. Specific mutations can also be determined through direct sequencing of one or both strands of DNA using dideoxy nucleotide chain termination chemistry, electrophoresis through a semi-solid matrix and fluorescent or radioactive chain length detection techniques. Further mutation detection techniques may involve differential susceptibility of the polymorphic double strand to restriction endonuclease digestion, or altered electrophoretic gel mobility of single or double stranded gene fragments containing one polymorphic form. Other techniques to detect specific DNA polymorphisms or mutation may involve evaluation of the structural characteristics at the site of polymorphism using nuclear magnetic resonance or x-ray diffraction techniques.

These genetic tests are useful for prognosing and/or diagnosing colorectal cancer and often are useful for determining whether an individual is at an increased or decreased risk of developing or having colorectal cancer.

Thus, the invention includes a method for identifying a subject at risk of colorectal cancer, which includes detecting in a nucleic acid sample from the subject the presence or absence of a SNP associated with colorectal cancer at a polymorphic site in a nucleotide sequence identified as SEQ ID NOs:1 to 1790.

Results from prognostic tests may be combined with other test results to diagnose colorectal cancer. For example, prognostic results may be gathered, a patient sample may be ordered based on a determined predisposition to colorectal cancer, the patient sample analyzed, and the results of the analysis may be utilized to diagnose colorectal cancer. Also colorectal cancer diagnostic methods can be developed from studies used to generate prognostic/diagnostic methods in which populations are stratified into subpopulations having different progressions of colorectal cancer. In another embodiment, prognostic results may be gathered; a patient's risk factors for developing colorectal cancer analyzed (e.g., age, family history); and a patient sample may be ordered based on a determined predisposition to colorectal cancer. In an alternative embodiment, the results from predisposition analyses may be combined with other test results indicative of colorectal cancer, which were previously, concurrently, or subsequently gathered with respect to the predisposition testing. In these embodiments, the combination of the prognostic test results with other test results can be probative of colorectal cancer, and the combination can be utilized as a colorectal cancer diagnostic.

Risk of colorectal cancer sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. The risk is based upon the presence or absence of one or more of the SNP variants described herein, and also may be based in part upon phenotypic traits of the individual being tested. Methods for calculating risk based upon patient data are well known (Agresti, 2001). Allelotyping and genotyping analyses may be carried out in populations other than those exemplified herein to enhance the predictive power of the prognostic method. These further analyses are executed in view of the exemplified procedures described herein, and may be based upon the same polymorphic variations or additional polymorphic variations. Risk determinations for colorectal cancer are useful in a variety of applications. In one embodiment, colorectal cancer risk determinations are used by clinicians to direct appropriate detection, preventative and treatment procedures to subjects who most require these. In another embodiment, colorectal cancer risk determinations are used by health insurers for preparing actuarial tables and for calculating insurance premiums.

The nucleic acid sample typically is isolated from a biological sample obtained from a subject. For example, nucleic acid can be isolated from blood, saliva, sputum, urine, cell scrapings, and biopsy tissue. The nucleic acid sample can be isolated from a biological sample using standard techniques. The nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.

The presence or absence of a polymorphic variant is determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic acid sample is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample. For example, primer extension methods, ligase sequence determination methods (e.g., U.S. Pat. Nos. 5,679,524 and 5,952,174, and WO 01/27326), mismatch sequence determination methods (e.g., U.S. Pat. Nos. 5,851,770; 5,958,692; 6,110,684; and 6,183,958), microarray sequence determination methods, restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499), PCR-based assays (e.g., TAQMAN™ PCR System (Applied Biosystems)), and nucleotide sequencing methods may be used.

Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PCR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation. One oligonucleotide primer is complementary to a region 3′ of the polymorphism and the other is complementary to a region 5′ of the polymorphism. A PCR primer pair may be used in methods disclosed in U.S. Pat. Nos. 4,683,195; 4,683,202, 4,965,188; 5,656,493; 5,998,143; 6,140,054; WO 01/27327; and WO 01/27329 for example. PCR primer pairs may also be used in any commercially available machines that perform PCR, such as any of the GENEAMP™, systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon the nucleotide sequences set forth in SEQ ID NOs:1 to 1790.

Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. An adjacent fragment refers to the 3′ end of the extension oligonucleotide being often 1 nucleotide from the 5′ end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5′ end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid. The extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present. Oligonucleotide extension methods are disclosed, for example, in U.S. Pat. Nos. 4,656,127; 4,851,331; 5,679,524; 5,834,189; 5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981,186; 6,004,744; 6,013,431; 6,017,702; 6,046,005; 6,087,095; 6,210,891; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos. 5,547,835; 5,605,798; 5,691,141; 5,849,542; 5,869,242; 5,928,906; 6,043,031; and 6,194,144. Multiple extension oligonucleotides may be utilized in one reaction, which is referred to as multiplexing.

A microarray can be utilized for determining whether a SNP is present or absent in a nucleic acid sample. A microarray may include any oligonucleotides described herein, and methods for making and using oligonucleotide microarrays suitable for diagnostic use are disclosed in U.S. Pat. Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940; 5,849,483; 6,018,041; 6,045,996; 6,136,541; 6,142,681; 6,156,501; 6,197,506; 6,223,127; 6,225,625; 6,229,911; 6,239,273; WO 00/52625; WO 01/25485; and WO 01/29259. The microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions. The oligonucleotides may also be linked to the solid support directly or by a spacer molecule. A microarray may comprise one or more oligonucleotides complementary to a SNP set forth in the tables.

A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit can include one or more pairs of oligonucleotide primers useful for amplifying a fragment of a nucleotide sequence of interest, where the fragment includes a polymorphic site. The kit sometimes comprises a polymerizing agent, for example, a thermo-stable nucleic acid polymerase such as one disclosed in U.S. Pat. No. 4,889,818 or 6,077,664. Also, the kit often comprises an elongation oligonucleotide that hybridizes to the nucleotide sequence in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it can also include chain elongating nucleotides, such as dATP, dTTP, dGTP, dCTP, and dITP, including analogs of dATP, dTTP, dGTP, dCTP and dITP, provided that such analogs are substrates for a thermo-stable nucleic acid polymerase and can be incorporated into a nucleic acid chain elongated from the extension oligonucleotide. Along with chain elongating nucleotides would be one or more chain terminating nucleotides such as ddATP, ddTTP, ddGTP, ddCTP. The kit can include one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides. Kits optionally include buffers, vials, microtiter plates, and instructions for use.

An individual identified as being susceptible to colorectal cancer may be heterozygous or homozygous with respect to the allele associated with an increased risk of colorectal cancer, as indicated in the tables. A subject homozygous for an allele associated with an increased risk of colorectal cancer is at a comparatively high risk of colorectal cancer as far as that SNP is concerned whether or not the allelic effect has been determined to be dominant or recessive. A subject who is heterozygous for an allele associated with an increased risk of colorectal cancer, in which the allelic effect is recessive would likely be at a comparatively reduced risk of colorectal cancer predicted by that SNP.

Individuals carrying mutations in one or more SNP of the present invention may be detected at the protein level by a variety of techniques. Cells suitable for diagnosis may be obtained from a patient's blood, urine, saliva, tissue biopsy and autopsy material.

Also featured are methods for determining risk of colorectal cancer and/or identifying a subject at risk of colorectal cancer by contacting a polypeptide or protein encoded by a nucleotide sequence from a subject with an antibody that specifically binds to an epitope associated with an altered, usually increased risk of colorectal cancer in the polypeptide.

Isolated Nucleic Acids

Oligonucleotides can be linked to a second moiety, which can be another nucleic acid molecule to provide, for example, a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), etc. Alternatively, the moiety might be one that facilitates linkage to a solid support or a detectable label, e.g., a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, etc.

Nucleic acid sequences shown in the tables can be used for diagnostic purposes for detection and control of polypeptide expression. Also, oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide are part of this invention.

Antisense RNA and DNA molecules, siRNA and ribozymes can be prepared by known methods. These include techniques for chemically synthesizing oligodeoxyribonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences can be incorporated into vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters, or antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.

DNA encoding a polypeptide can also be used in the diagnosis of colorectal cancer, resulting from aberrant expression of a target gene. For example, the nucleic acid sequence can be used in hybridization assays of biopsies or autopsies to diagnose abnormalities of expression or function (e.g., Southern or Northern blot analysis, in situ hybridization assays).

Expression of a polypeptide during embryonic development can also be determined using nucleic acid encoding the polypeptide, particularly production of a functionally impaired polypeptide that is the cause of colorectal cancer. In situ hybridizations using a polypeptide as a probe can be employed to predict problems related to colorectal cancer. Administration of human active polypeptide, recombinantly produced can be used to treat disease states related to functionally impaired polypeptide. Alternatively, gene therapy approaches may be employed to remedy deficiencies of functional polypeptide or to replace or compete with a dysfunctional polypeptide.

Included as part of this invention are nucleic acid vectors, often expression vectors, which contain a nucleotide sequence set forth in the tables. A vector is a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid, or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors may include replication defective retroviruses, adenoviruses and adeno-associated viruses for example.

A vector can include a nucleotide sequence from the tables in a form suitable for expression of an encoded protein or nucleic acid in a host cell. The recombinant expression vector generally includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. A regulatory sequence includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences. The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, etc. Expression vectors can be introduced into host cells to produce the desired polypeptides, including fusion polypeptides.

Recombinant expression vectors can be designed for expression of polypeptides in prokaryotic or eukaryotic cells. For example, the polypeptides can be expressed in E. coli, insect cells (e.g., using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further by Goeddel (Goeddel, 1990). A recombinant expression vector can also be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of polypeptides in prokaryotes can be carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion polypeptides. Fusion vectors add a number of amino acids to a polypeptide. Such fusion vectors typically serve to increase expression of recombinant polypeptide, to increase the solubility of the recombinant polypeptide and/or to aid in the purification of the recombinant polypeptide by acting as a ligand during purification. Often, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety after purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; (Smith & Johnson, 1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.

Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector can be used to infect bone marrow cells that are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed.

Expressing a polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide can be used to maximize recombinant polypeptide expression (Gottesman, 1990). The nucleotide sequence of the nucleic acid to be inserted into an expression vector can be changed so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., 1992).

When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. Recombinant mammalian expression vectors can be capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Examples of suitable tissue-specific promoters include an albumin promoter (Pinkert et al., 1987), lymphoid-specific promoters (Calame and Eaton, 1988), promoters of immunoglobulins (Banerji et al., 1983; Queen and Baltimore, 1983), neuron-specific promoters (Byrne and Ruddle, 1989), pancreas-specific promoters (Edlund et al., 1985), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (Kessel and Gruss, 1990) and the .alpha.-fetopolypeptide promoter (Camper and Tilghman, 1989).

A nucleic acid from one of the tables might be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a nucleic acid cloned in the antisense orientation can be chosen for directing constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types. Antisense expression vectors can be in the form of a recombinant plasmid, phagemid or attenuated virus.

The invention includes host cells having a nucleotide sequence from the tables within a recombinant expression vector or a fragment of such a sequence, which facilitate homologous recombination into a specific site of the host cell genome. Terms such as host cell and recombinant host cell refer not only to the particular subject cell but also to the progeny of a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell. A host cell can be any prokaryotic or eukaryotic cell. For example, a polypeptide can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells).

Vectors can be introduced into host cells via conventional transformation or transfection techniques. The terms transformation and transfection refer to a variety of techniques known for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transduction/infection, DEAE-dextran-mediated transfection, lipofection, or electroporation.

A host cell can be used to produce a polypeptide. Accordingly, methods for producing a polypeptide using the host cells are included as part of this invention. Such a method can include culturing host cells into which a recombinant expression vector encoding a polypeptide has been introduced in a suitable medium such that the polypeptide is produced. The method can further include isolating the polypeptide from the medium or the host cell.

The invention also includes cells or purified preparations of cells which include a transgene from the tables, or which otherwise mis-express a polypeptide. Cell preparations can consist of human or non-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. The transgene can be mis-expressed, e.g., over-expressed or under-expressed. In other embodiments, the cell or cells include a gene which misexpresses an endogenous polypeptide (e.g., expression of a gene is disrupted, also known as a knockout). Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed alleles or for use in drug screening. Also provided are human cells (e.g., hematopoietic stem cells) transformed with a nucleic acid from the tables.

The invention includes cells or a purified preparation thereof (e.g., human cells) in which an endogenous nucleic acid from the tables is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene corresponding to the sequence. The expression characteristics of an endogenous gene within a cell (e.g., a cell line or microorganism) can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the corresponding endogenous gene. For example, an endogenous corresponding gene (e.g., a gene which is transcriptionally silent, not normally expressed, or expressed only at very low levels) may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published on May 16, 1991.

Non-human transgenic animals that express a heterologous polypeptide (e.g., expressed from a nucleic acid from the tables) can be generated. Such animals are useful for studying the function and/or activity of a polypeptide and for identifying and/or evaluating modulators of the activity of the nucleic acids and encoded polypeptides. A transgenic animal is a non-human animal such as a mammal (e.g., a non-human primate such as chimpanzee, baboon, or macaque; an ungulate such as an equine, bovine, or caprine; or a rodent such as a rat, a mouse, or an Israeli sand rat), a bird (e.g., a chicken or a turkey), an amphibian (e.g., a frog, salamander, or newt), or an insect (e.g., Drosophila melanogaster), in which one or more of the cells of the animal includes a transgene. A transgene is exogenous DNA or a rearrangement (e.g., a deletion of endogenous chromosomal DNA) that is often integrated into or occurs in the genome of cells in a transgenic animal. A transgene can direct expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a nucleic acid from the tables has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal (e.g., an embryonic cell of the animal) prior to development of the animal.

Intronic sequences and polyadenylation signals can also be included in the transgene to increase expression efficiency of the transgene. One or more tissue-specific regulatory sequences can be operably linked to a nucleotide sequence from the tables to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of the nucleotide sequence in its genome and/or expression of encoded mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a nucleotide sequence can further be bred to other transgenic animals carrying other transgenes.

Polypeptides can be expressed in transgenic animals or plants by introducing a nucleic acid encoding the polypeptide into the genome of an animal. In certain embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Also included is a population of cells from a transgenic animal.

Isolated polypeptides encoded by a nucleotide sequence from the tables can be synthesized. Isolated polypeptides include both the full-length polypeptide and the mature polypeptide (i.e., the polypeptide minus the signal sequence or propeptide domain). An isolated, or purified, polypeptide or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or is substantially free from chemical precursors or other chemicals when chemically synthesized. Substantially free means a preparation of a polypeptide having less than about 5% (by dry weight) of contaminating protein, or of chemical precursors or non-target chemicals. When the desired polypeptide is recombinantly produced, it is typically substantially free of culture medium, specifically, where culture medium represents less than about 10% of the polypeptide preparation.

Also, polypeptides may exist as chimeric or fusion polypeptides. As used herein, a “target chimeric polypeptide” or “target fusion polypeptide” includes a target polypeptide linked to a different polypeptide. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire polypeptide as it exists in nature or a fragment thereof. The other polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.

Fusion polypeptides can include a moiety having high affinity for a ligand. For example, the fusion polypeptide can be a GST-target fusion polypeptide in which the target sequences are fused to the C-terminus of the GST sequences, or a polyhistidine-target fusion polypeptide in which the target polypeptide is fused at the N- or C-terminus to a string of histidine residues. Such fusion polypeptides can facilitate purification of recombinant target polypeptide. Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide), and a nucleotide sequence from the tables, or a substantially identical nucleotide sequence thereof, can be cloned into an expression vector such that the fusion moiety is linked in-frame to the target polypeptide. Further, the fusion polypeptide can be a target polypeptide containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression, secretion, cellular internalization, and cellular localization of a target polypeptide can be increased through use of a heterologous signal sequence. Fusion polypeptides can also include all or a part of a serum polypeptide (e.g., an IgG constant region or human serum albumin).

Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these polypeptides can be used to affect the bioavailability of a substrate of the polypeptide and may effectively increase polypeptide biological activity in a cell. Target fusion polypeptides may be useful therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a polypeptide; (ii) mis-regulation of the gene encoding the polypeptide; and (iii) aberrant post-translational modification of a polypeptide. Also, target polypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify the polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a polypeptide with a substrate.

Polypeptides can be differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any known modification including specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH₄; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc. may be used. Additional post-translational modifications include, for example, N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide.

Chemically modified derivatives of polypeptides that can provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see e.g., U.S. Pat. No. 4,179,337) are also part of this invention. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the molecular weight often is between about 1 kDa and about 100 kDa for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).

The polymers can be attached to the polypeptide with consideration of effects on functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art (e.g., EP 0 401 384 (coupling PEG to G-CSF) and Malik et al. (Malik et al., 1992) For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. For therapeutic purposes, the attachment sometimes is at an amino group, such as attachment at the N-terminus or lysine group.

Proteins can be chemically modified at the N-terminus. Using polyethylene glycol, for example, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, and the like), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus may be accomplished by reductive alkylation, which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achievable.

Applications of Prognostic and Diagnostic Results to Pharmacogenomic Methods

Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype. For example, based upon the outcome of a prognostic test, a clinician or physician may target pertinent information and preventative or therapeutic treatments to a subject who would be benefited by the information or treatment and avoid directing such information and treatments to a subject who would not be benefited (e.g., the treatment has no therapeutic effect and/or the subject experiences adverse side effects). As therapeutic approaches for colorectal cancer continue to evolve and improve, the goal of treatments for colorectal cancer related disorders is to intervene even before clinical signs manifest themselves. Thus, genetic markers associated with susceptibility to colorectal cancer prove useful for early diagnosis, prevention and treatment of colorectal cancer.

The following is an example of a pharmacogenomic embodiment. A particular treatment regimen can exert a differential effect depending upon the subject's genotype. Where a candidate therapeutic exhibits a significant beneficial interaction with a prevalent allele and a comparatively weak interaction with an uncommon allele (e.g., an order of magnitude or greater difference in the interaction), such a therapeutic typically would not be administered to a subject genotyped as being homozygous for the uncommon allele, and sometimes not administered to a subject genotyped as being heterozygous for the uncommon allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a prevalent allele but is comparatively toxic when administered to subjects heterozygous or homozygous for an uncommon allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the uncommon allele.

Methods of the invention are applicable to pharmacogenomic methods for detecting, preventing, alleviating and/or treating colorectal cancer. For example, a nucleic acid sample from an individual may be subjected to a genetic test. Where one or more SNPs associated with increased risk of colorectal cancer are identified in a subject, information for detecting, preventing or treating colorectal cancer and/or one or more colorectal cancer detection, prevention and/or treatment regimens then may be directed to and/or prescribed to that subject.

In certain embodiments, a detection, preventative and/or treatment regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing colorectal cancer assessed by the methods described herein. Methods are thus provided for identifying a subject at risk of colorectal cancer and then prescribing a detection, therapeutic or preventative regimen to individuals identified as being at increased risk of colorectal cancer. Thus, certain embodiments are directed to methods for treating colorectal cancer in a subject, reducing risk of colorectal cancer in a subject, or early detection of colorectal cancer in a subject, which comprise: detecting the presence or absence of a SNP associated with colorectal cancer in a nucleotide sequence set forth in SEQ ID NOs:1 to 1790, and prescribing or administering a colorectal cancer treatment regimen, preventative regimen and/or detection regimen to a subject from whom the sample originated where the presence of one or more SNPs associated with colorectal cancer are detected in the nucleotide sequence. In these methods, genetic results may be utilized in combination with other test results to diagnose colorectal cancer as described above.

The use of certain colorectal cancer treatments are known in the art, and include surgery, chemotherapy and/or radiation therapy. Any of the treatments may be used in combination to treat or prevent colorectal cancer (e.g., surgery followed by radiation therapy or chemotherapy).

Pharmacogenomic methods also may be used to analyze and predict a response to a colorectal cancer treatment or a drug. For example, if pharmacogenomic analysis indicates a likelihood that an individual will respond positively to a colorectal cancer treatment with a particular drug, the drug may be administered to the individual. Conversely, if the analysis indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects. The response to a therapeutic treatment can be predicted in a background study in which subjects in any of the following populations are genotyped: a population that responds favorably to a treatment regimen, a population that does not respond significantly to a treatment regimen, and a population that responds adversely to a treatment regiment (e.g., exhibits one or more side effects). These populations are provided as examples and other populations and subpopulations may be analyzed. Based upon the results of these analyses, a subject is genotyped to predict whether he or she will respond favorably to a treatment regimen, not respond significantly to a treatment regimen, or respond adversely to a treatment regimen.

The methods described herein also are applicable to clinical drug trials. One or more SNPs indicative of response to an agent for treating colorectal cancer or to side effects to an agent for treating colorectal cancer may be identified. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as a result of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems. Thus, another embodiment is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of: (a) obtaining a nucleic acid sample from an individual; (b) determining the identity of a polymorphic variant, e.g., SNP which is associated with a positive response to the treatment or the drug, or at least one SNP which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and (c) including the individual in the clinical trial if the nucleic acid sample contains the SNP associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said SNP associated with a negative response to the treatment or the drug. The SNP may be in a sequence selected individually or in any combination from those disclosed in the tables. Step (c) can also include administering the drug or the treatment to the individual if the nucleic acid sample contains the SNP associated with a positive response to the treatment or the drug and the nucleic acid sample lacks the SNP associated with a negative response to the treatment or the drug.

Compositions Comprising Colorectal Cancer-Directed Molecules

The invention includes a composition made up of a colorectal cancer cell and one or more molecules specifically directed and targeted to a nucleic acid comprising a nucleotide sequence shown in the tables, or a polypeptide encoded thereby. Such directed molecules include, but are not limited to, a compound that binds to a nucleic acid or a polypeptide; a RNAi or siRNA molecule having a strand complementary to a nucleotide sequence; an antisense nucleic acid complementary to an RNA encoded by a DNA sequence; a ribozyme that hybridizes to a nucleotide sequence; a nucleic acid aptamer that specifically binds a polypeptide; and an antibody that specifically binds to a polypeptide or binds to a nucleic acid. In specific embodiments, the colorectal cancer directed molecule interacts with a nucleic acid or polypeptide variant associated with colorectal cancer.

Compounds

Compounds can be obtained using any of numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive (Zuckermann et al., 1994). Biological library and peptoid library approaches are typically limited to peptide libraries, while the other approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997). Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al. (DeWitt et al., 1993), Erb et al. (Erb et al., 1994), Zuckermann et al. (Zuckermann et al., 1994), Cho et al. (Cho et al., 1993) and Gallop et al. (Gallop et al., 1994).

Libraries of compounds may be presented in solution (Houghten et al., 1992), or on beads (Lam et al., 1991), chips (Fodor et al., 1993), bacteria or spores (Ladner, U.S. Pat. No. 5,223,409), plasmids (Cull et al., 1992) or on phage (Scott and Smith, 1990; Devlin et al., 1990; Cwirla et al., 1990; Felici et al., 1991).

A compound sometimes alters expression and sometimes alters activity of a target polypeptide and may be a small molecule. Small molecules include peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

An antisense nucleic acid refers to a nucleotide sequence complementary to a sense nucleic acid encoding a polypeptide, e.g., complementary to the, coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire coding strand in a nucleic acid molecule having a sequence of one of SEQ ID NOs:1761 to 1790, or to a portion thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a non-coding region of the coding strand of a nucleotide sequence, e.g., 5′ and 3′ untranslated regions.

An antisense nucleic acid can be designed such that it is complementary to the entire coding region of an mRNA encoded by a nucleotide sequence of interest, and often the antisense nucleic acid is an oligonucleotide antisense to only a portion of a coding or non-coding region of the mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of the mRNA, e.g., between the −10 and +10 regions of the target gene nucleotide (SNP) sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length. The antisense nucleic acids, which include the ribozymes described below, can be designed to target a nucleotide sequence in any of SEQ ID NOs:1761 to 1790. Uncommon alleles and prevalent alleles can be targeted, and those associated with an increased risk of colorectal cancer are often designed, tested, and administered to subjects.

An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid molecule can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest.

When utilized as therapeutics, antisense nucleic acids typically are administered to a subject (e.g., by direct injection at a tissue site) or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide and thereby inhibit expression of the polypeptide, for example, by inhibiting transcription and/or translation. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then are administered systemically. For systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. Antisense nucleic acid molecules can also be delivered to cells using vectors. Sufficient intracellular concentrations of antisense molecules are achieved by incorporating a strong promoter, such as a pol II or pol III promoter, in the vector construct.

Antisense nucleic acid molecules sometimes are anomeric nucleic acid molecules (Gautier et al., 1987). Antisense nucleic acid molecules can also comprise a 2′-o-methylribonucleotide (Inoue et al., 1987a) or a chimeric RNA-DNA analogue (Inoue et al., 1987b). Antisense nucleic acids sometimes are composed of DNA or peptide nucleic acid (PNA).

In another embodiment, an antisense nucleic acid is a ribozyme. A ribozyme having specificity for a target nucleotide sequence can include one or more sequences complementary to such a nucleotide sequence, and a sequence having a known catalytic region responsible for mRNA cleavage (see e.g., U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach (Haseloff and Gerlach, 1988). For example, a derivative of a Tetrahymena L-19 IVS RNA is sometimes utilized in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA (see e.g., Cech et al., U.S. Pat. No. 4,987,071; and Cech et al., U.S. Pat. No. 5,116,742). Also, target mRNA sequences can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules (Bartel and Szostak, 1993).

Colorectal cancer directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a target nucleotide sequence, especially one that includes a regulatory region that controls expression of a polypeptide. Gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a target nucleotide sequence (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells (Helene, 1991; Helene et al., 1992; Maher, III, 1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a switchback nucleic acid molecule. Switchback molecules are synthesized in an alternating 5′-3′,3′-5′ manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.

Colorectal cancer directed molecules include RNAi and siRNA nucleic acids. Gene expression may be inhibited by the introduction of double-stranded RNA (dsRNA), which induces potent and specific gene silencing, a phenomenon called RNA interference or RNAi. See, e.g., Fire et al., U.S. Pat. No. 6,506,559; Tuschl et al., PCT International Publication No. WO 01/75164; Kay et al., PCT International Publication No. WO 03/010180A1; or Bosher J M, Labouesse (Bosher and Labouesse, 2000). This process has been improved by decreasing the size of the double-stranded RNA to 20-24 base pairs (to create small-interfering RNAs or siRNAs) that switched off genes in mammalian cells without initiating an acute phase response, i.e., a host defense mechanism that often results in cell death (Caplen et al., 2001a; Elbashir et al., 2002). There is increasing evidence of post-transcriptional gene silencing by RNA interference (RNAi) for inhibiting targeted expression in mammalian cells at the mRNA level, in human cells. There is additional evidence of effective methods for inhibiting the proliferation and migration of tumor cells in human patients, and for inhibiting metastatic cancer development (see, e.g., U.S. patent application No. US2001000993183; Caplen et al. (Caplen et al., 2001b), Abderrahman et al. (Abderrahmani et al., 2001).

An siRNA or RNAi is a nucleic acid that forms a double stranded RNA and has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is delivered to or expressed in the same cell as the gene or target gene. siRNA is short double-stranded RNA formed by the complementary strands. Complementary portions of the siRNA that hybridize to form the double stranded molecule often have substantial or complete identity to the target molecule sequence. In one embodiment, an siRNA is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA.

When designing the siRNA molecules, the targeted region often is selected from a given DNA sequence beginning 50 to 100 nucleotides downstream of the start codon. See, e.g., Elbashir et al. (Elbashir et al., 2002). Initially, 5′ or 3′ UTRs and regions nearby the start codon were avoided assuming that UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. Sometimes regions of the target 23 nucleotides in length conforming to the sequence motif AA (N19)TT (N, an nucleotide), and regions with approximately 30% to 70% G/C-content (often about 50% G/C-content) often are selected. If no suitable sequences are found, the search often is extended using the motif NA (N2 1). The sequence of the sense siRNA sometimes corresponds to (N19) TT or N21 (position 3 to 23 of the 23-nt motif), respectively. In the latter case, the 3′ end of the sense siRNA often is converted to TT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3′ overhangs. The antisense siRNA is synthesized as the complement to position 1 to 21 of the 23-nt motif. Because position 1 of the 23-nt motif is not recognized sequence-specifically by the antisense siRNA, the 3′-most nucleotide residue of the antisense siRNA can be chosen deliberately. However, the penultimate nucleotide of the antisense siRNA (complementary to position 2 of the 23-nt motif) often is complementary to the targeted sequence. For simplifying chemical synthesis, TT often is utilized. siRNAs corresponding to the target motif NAR (N17)YNN, where R is purine (A,G) and Y is pyrimidine (C,U), often are selected. Respective 21 nucleotide sense and antisense siRNAs often begin with a purine nucleotide and can also be expressed from pol III expression vectors without a change in targeting site. Expression of RNAs from pol III promoters can be more efficient when the first transcribed nucleotide is a purine.

The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof. Often, the siRNA is about 15 to about 50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15 to 50 nucleotides in length, and the double stranded siRNA is about 15 to 50 base pairs in length, sometimes about 20 to 30 nucleotides in length or about 20 to 25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. The siRNA sometimes is about 21 nucleotides in length. Methods of using siRNA are known in the art, and specific siRNA molecules may be purchased from a number of companies including Dharmacon Research, Inc.

Antisense, ribozyme, RNAi and siRNA nucleic acids can be altered to form modified nucleic acid molecules. The nucleic acids can be altered at base moieties, sugar moieties or phosphate backbone moieties to improve stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of nucleic acid molecules can be modified to generate peptide nucleic acids (see Hyrup et al., Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)). A peptide nucleic acid, or PNA, refers to a nucleic acid mimic such as a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can allow for specific hybridization to DNA and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described, for example, in Hyrup et al. (Hyrup and Nielsen, 1996), and Perry-O'Keefe et al. (Abderrahmani et al., 2001).

PNA nucleic acids can be used in prognostic, diagnostic, and therapeutic applications. For example, PNAs can be used as anti-sense or anti-gene agents for sequence-specific modulation of gene expression by, for example, inducing transcription or translation arrest or inhibiting replication. PNA nucleic acid molecules can also be used in the analysis of SNPs in a gene, (e.g., by PNA-directed PCR clamping); as artificial restriction enzymes when used in combination with other enzymes, (e.g., S1 nucleases (Hyrup and Nielsen, 1996) or as probes or primers for DNA sequencing or hybridization (Hyrup and Nielsen, 1996; Perry-O'Keefe et al., 1996).

In other embodiments, oligonucleotides may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across cell membranes (see e.g., Letsinger et al. (Letsinger et al., 1989); Lemaitre et al. (Lemaitre et al., 1987) and PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (van der Krol et al., 1988) or intercalating agents (Zon, 1988). To this end, the oligonucleotide may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).

Also included as part of this invention are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a target nucleotide sequence, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantifying the presence of the nucleic acid in a sample. Molecular beacon nucleic acids are described, for example, in Lizardi et al., U.S. Pat. No. 5,854,033; Nazarenko et al., U.S. Pat. No. 5,866,336, and Livak et al., U.S. Pat. No. 5,876,930.

Antibodies

An immunogen typically is used to prepare antibodies by immunizing a suitable subject, (e.g., rabbit, goat, mouse or other mammal). An appropriate immunogenic preparation can contain, for example, recombinantly expressed chemically synthesized polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent. Amino acid polymorphisms can be detected using antibodies specific for the altered epitope by western analysis after the electrophoresis of denatured proteins. Protein polymorphism can also be detected using fluorescently identified antibodies which bind to specific polymorphic epitopes and detected in whole cells using fluorescence activated cell sorting techniques (FACS). Polymorphic protein sequence may also be determined by NMR spectroscopy or by x-ray diffraction studies. Further, determination of polymorphic sites in proteins may be accomplished by observing differential cleavage by specific or non specific proteases.

An antibody is an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab′)₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody can be polyclonal, monoclonal, or recombinant (e.g., a chimeric or humanized), fully human, non-human (e.g., murine), or a single chain antibody. An antibody may have effector function and can fix complement, and is sometimes coupled to a toxin or imaging agent.

A full-length polypeptide or antigenic peptide fragment encoded by a target nucleotide sequence can be used as an immunogen or can be used to identify antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. An antigenic peptide often includes at least 8 amino acid residues of the amino acid sequences encoded by a nucleotide sequence of one of SEQ ID NOs:1761 to 1790, and encompasses an epitope. Antigenic peptides sometimes include 10 or more amino acids, 15 or more amino acids, 20 or more amino acids, or 30 or more amino acids. Hydrophilic and hydrophobic fragments of polypeptides sometimes are used as immunogens.

Epitopes encompassed by the antigenic peptide are regions located on the surface of the polypeptide (e.g., hydrophilic regions) as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human polypeptide sequence can be used to indicate the regions that have a particularly high probability of being localized to the surface of the polypeptide and are thus likely to constitute surface residues useful for targeting antibody production. The antibody may bind an epitope on any domain or region on polypeptides for use in the invention.

Also, chimeric, humanized, and completely human antibodies are useful for applications which include repeated administration to subjects. Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques, for example using methods described in Robinson et al., International Application No. PCT/US86/02269; Akira, et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., PCT International Publication No. WO 86/01533; Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., European Patent Application 125,023; (Better et al., 1988; Liu et al., 1987a; Liu et al., 1987b; Sun et al., 1987; Nishimura et al., 1987; Wood et al., 1985; Shaw et al., 1988; Morrison, 1985; Verhoeyen et al., 1988; Beidler et al., 1988) and Winter, U.S. Pat. No. 5,225,539.

Completely human antibodies can be particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar (Lonberg and Huszar, 1995) and U.S. Pat. Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Fremont, Calif.) and Medarex, Inc. (Princeton, N.J.), can be engaged to provide human antibodies directed against a selected antigen. Completely human antibodies that recognize a selected epitope also can be generated using guided selection. In this approach a selected non-human monoclonal antibody (e.g., a murine antibody) is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described for example by Jespers et al. (Jespers et al., 1994).

An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al. (Colcher et al., 1999) and Reiter (Reiter and Pastan, 1996). Single chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.

Antibodies also may be selected or modified so that they exhibit reduced or no ability to bind an Fc receptor. For example, an antibody may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor (e.g., it has a mutagenized or deleted Fc receptor binding region).

Also, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1 dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

Antibody conjugates can be used for modifying a given biological response. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, γ-interferon, α-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors. Also, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, for example.

An antibody (e.g., monoclonal antibody) can be used to isolate target polypeptides by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, an antibody can be used to detect a target polypeptide (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H. Also, an antibody can be utilized as a test molecule for determining whether it can treat colorectal cancer, and as a therapeutic for administration to a subject for treating colorectal cancer.

An antibody can be made by immunizing with a purified antigen, or a fragment thereof, a membrane associated antigen, tissues, e.g., crude tissue preparations, whole cells, preferably living cells, lysed cells, or cell fractions.

Included as part of this invention are antibodies which bind only a native polypeptide, only denatured or otherwise non-native polypeptide, or which bind both, as well as those having linear or conformational epitopes. Conformational epitopes sometimes can be identified by selecting antibodies that bind to native but not denatured polypeptide. Also featured are antibodies that specifically bind to a polypeptide variant associated with colorectal cancer.

Screening Assays

The invention includes methods for identifying a candidate therapeutic for treating colorectal cancer. The methods include contacting a test molecule with a target molecule in a system. A target molecule is a nucleic acid molecule having a sequence of any of SEQ ID NOs:1 to 1790, or a fragment thereof, or an encoded polypeptide of SEQ ID NOs:1761 to 1790. The method also includes determining the presence or absence of an interaction between the test molecule and the target molecule, where the presence of an interaction between the test molecule and the nucleic acid or polypeptide identifies the test molecule as a candidate colorectal cancer therapeutic. The interaction between the test molecule and the target molecule may be quantified.

Test molecules and candidate therapeutics include compounds, antisense nucleic acids, siRNA molecules, ribozymes, polypeptides or proteins encoded by target nucleic acids, and immunotherapeutics (e.g., antibodies and HLA-presented polypeptide fragments). A test molecule or candidate therapeutic may act as a modulator of target molecule concentration or target molecule function in a system. A modulator may agonize (i.e., up-regulates) or antagonize (i.e., down-regulates) a target molecule concentration partially or completely in a system by affecting such cellular functions as DNA replication and/or DNA processing (e.g., DNA methylation or DNA repair), RNA transcription and/or RNA processing (e.g., removal of intronic sequences and/or translocation of spliced mRNA from the nucleus), polypeptide production (e.g., translation of the polypeptide from mRNA), and/or polypeptide post-translational modification (e.g., glycosylation, phosphorylation, and proteolysis of pro-polypeptides). A modulator may also agonize or antagonize a biological function of a target molecule partially or completely, where the function may include adopting a certain structural conformation, interacting with one or more binding partners, ligand binding, catalysis (e.g., phosphorylation, dephosphorylation, hydrolysis, methylation, and isomerization), and an effect upon a cellular event (e.g., effecting progression of colorectal cancer).

According to an aspect of this invention a system, i.e., a cell free in vitro environment and a cell-based environment such as a collection of cells, a tissue, an organ, or an organism, is contacted with a test molecule in a variety of manners, including adding molecules in solution and allowing them to interact with one another by diffusion, cell injection, and any administration routes in an animal. An interaction refers to an effect of a test molecule on test molecule, where the effect sometimes is binding between the test molecule and the target molecule, and sometimes is an observable change in cells, tissue, or organism.

There are known methods for detecting the presence or absence of interaction between a test molecule and a target molecule. For example, titrametric, acidimetric, radiometric, NMR, monolayer, polarographic, spectrophotometric, fluorescent, and ESR assays probative of a target molecule interaction may be utilized.

Test molecule/target molecule interactions can be detected and/or quantified using known assays. For example, an interaction can be determined by labeling the test molecule and/or the target molecule, where the label is covalently or non-covalently attached to the test molecule or target molecule. The label is sometimes a radioactive molecule such as ¹²⁵I, ¹³¹I, ³⁵S or ³H, which can be detected by direct counting of radio-emission or by scintillation counting. Also, enzymatic labels such as horseradish peroxidase, alkaline phosphatase, or luciferase may be utilized where the enzymatic label can be detected by determining conversion of an appropriate substrate to product. In addition, presence or absence of an interaction can be determined without labeling. For example, a microphysiometer (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indication of an interaction between a test molecule and target molecule (McConnell et al., 1992).

In cell-based systems, cells typically include a nucleic acid from SEQ ID NOs:1 to 1790 or an encoded polypeptide from SEQ ID NOs:1761 to 1790, and are often of mammalian origin, although the cell can be of any origin. Whole cells, cell homogenates, and cell fractions (e.g., cell membrane fractions) can be subjected to analysis. Where interactions between a test molecule with a target polypeptide are monitored, soluble and/or membrane bound forms of the polypeptide may be utilized. Where membrane-bound forms of the polypeptide are used, it may be desirable to utilize a solubilizing agent. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, TritonTMX-100, Triton™ X-114, etc.

An interaction between a test molecule and target molecule also can be detected by monitoring fluorescence energy transfer (FET) (see, e.g., Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos et al., U.S. Pat. No. 4,868,103). A fluorophore label on a first, donor molecule is selected such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, acceptor molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the donor polypeptide molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the acceptor molecule label may be differentiated from that of the donor. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the acceptor molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

In another embodiment, determining the presence or absence of an interaction between a test molecule and a target molecule can be effected by monitoring surface plasmon resonance (Sjolander and Urbaniczky, 1991; Szabo et al., 1995). Surface plasmon resonance (SPR) or biomolecular interaction analysis (BIA) can be utilized to detect biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance, resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

In another embodiment, the target molecule or test molecules are anchored to a solid phase, facilitating the detection of target molecule/test molecule complexes and separation of the complexes from free, uncomplexed molecules. The target molecule or test molecule is immobilized to the solid support. In one embodiment, the target molecule is anchored to a solid surface, and the test molecule, which is not anchored, can be labeled, either directly or indirectly, with detectable labels.

It may be desirable to immobilize a target molecule, an anti-target molecule antibody, and/or test molecules to facilitate separation of target molecule/test molecule complexes from uncomplexed forms, as well as to accommodate automation of the assay. The attachment between a test molecule and/or target molecule and the solid support may be covalent or non-covalent (see, e.g., U.S. Pat. No. 6,022,688 for non-covalent attachments). The solid support may be one or more surfaces of the system, such as one or more surfaces in each well of a microtiter plate, a surface of a silicon wafer, a surface of a bead (Lam et al., 1991) that is optionally linked to another solid support, or a channel in a microfluidic device, for example. Types of solid supports, linker molecules for covalent and non-covalent attachments to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are known (see, e.g., U.S. Pat. Nos. 6,261,776; 5,900,481; 6,133,436; and 6,022,688; and WIPO publication WO 01/18234).

In one embodiment, a target molecule may be immobilized to surfaces via biotin and streptavidin. For example, a biotinylated polypeptide can be prepared from biotin-NHS (N-hydroxysuccinimide, e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In another embodiment, a target polypeptide can be prepared as a fusion polypeptide. For example, glutathione-S-transferase/-polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, which are then combined with a test molecule under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, or the matrix is immobilized in the case of beads, and complex formation is determined directly or indirectly as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of target molecule binding or activity is determined using standard techniques.

In one embodiment, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that a significant percentage of complexes formed will remain immobilized to the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of manners. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface, e.g., by adding a labeled antibody specific for the immobilized component, where the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody.

In another embodiment, an assay is performed utilizing antibodies that specifically bind a target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule. Such antibodies can be linked to a solid support, and unbound target molecule may be immobilized by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by known techniques, including: differential centrifugation (Rivas and Minton, 1993); electrophoresis (1999) and immunoprecipitation (1999). Media and chromatographic techniques are known (Heegaard, 1998; Hage and Tweed, 1997). Further, fluorescence energy transfer may also be conveniently utilized to detect binding without further purification of the complex from solution.

In another embodiment, modulators of target molecule expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of target mRNA or polypeptide is evaluated relative to the level of expression of target mRNA or polypeptide in the absence of the candidate compound. When expression of target mRNA or polypeptide is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as an agonist of target mRNA or polypeptide expression. Alternatively, when expression of target mRNA or polypeptide is less (e.g., less with statistical significance) in the presence of the candidate compound than in its absence, the candidate compound is identified as an antagonist or inhibitor of target mRNA or polypeptide expression. The level of target mRNA or polypeptide expression can be determined by methods described herein.

In another embodiment, binding partners that interact with a target molecule are detected. The target molecules can interact with one or more cellular or extra-cellular macromolecules, such as polypeptides in vivo, and these interacting molecules or binding partners. Binding partners can agonize or antagonize target molecule biological activity. Also, test molecules that agonize or antagonize interactions between target molecules and binding partners can be useful as therapeutic molecules as they can up-regulate or down-regulated target molecule activity in vivo and thereby treat colorectal cancer.

Binding partners of target molecules can be identified by known methods. For example, binding partners may be identified by lysing cells and analyzing cell lysates by electrophoretic techniques. Alternatively, a two-hybrid assay or three-hybrid assay can be utilized (Zervos et al., 1993; Madura et al., 1993; Bartel et al., 1993; Iwabuchi et al., 1993): see also, e.g., U.S. Pat. No. 5,283,317 and Brent WO94/10300. A two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. The assay often utilizes two different DNA constructs. In one construct, a nucleic acid from one of SEQ ID NOs:1761 to 1790, sometimes referred to as the bait, is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In another construct, a DNA sequence from a library of DNA sequences that encodes a potential binding partner, sometimes referred to as the prey, is fused to a gene that encodes an activation domain of the known transcription factor. Sometimes, a target nucleic acid can be fused to the activation domain. If the bait and the prey molecules interact in vivo, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., lacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to identify the potential binding partner.

In an embodiment for identifying test molecules that antagonize or agonize complex formation between target molecules and binding partners, a reaction mixture containing the target molecule and the binding partner is prepared, under conditions and for a time sufficient to allow complex formation. The reaction mixture often is provided in the presence or absence of the test molecule. The test molecule can be included initially in the reaction mixture, or can be added at a time subsequent to the addition of the target molecule and its binding partner. Control reaction mixtures are incubated without the test molecule or with a placebo. Formation of any complexes between the target molecule and the binding partner then is detected. Decreased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule antagonizes target molecule/binding partner complex formation. Alternatively, increased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture, indicates that the molecule agonizes target molecule/binding partner complex formation. In another embodiment, complex formation of target molecule/binding partner can be compared to complex formation of mutant target molecule/binding partner (e.g., amino acid modifications in a target polypeptide). Such a comparison can be important in those cases where it is desirable to identify test molecules that modulate interactions of mutant but not non-mutated target gene products.

The assays can be conducted in a heterogeneous or homogeneous format. In heterogeneous assays, a target molecule and/or the binding partner are immobilized to a solid phase, and complexes are detected on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the molecules being tested. For example, test compounds that agonize target molecule/binding partner interactions can be identified by conducting the reaction in the presence of the test molecule in a competition format. Alternatively, test molecules that agonize preformed complexes, e.g., molecules with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed.

In a heterogeneous assay, the target molecule or the binding partner is anchored onto a solid surface (e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored molecule can be immobilized by non-covalent or covalent attachments. Alternatively, an immobilized antibody specific for the molecule to be anchored can be used to anchor the molecule to the solid surface. The partner of the immobilized species is exposed to the coated surface with or without the test molecule. After the reaction is complete, unreacted components are removed (e.g., by washing) such that a significant portion of any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface is indicative of complex. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored to the surface; e.g., by using a labeled antibody specific for the initially non-immobilized species. Depending upon the order of addition of reaction components, test compounds that inhibit complex formation or that disrupt preformed complexes can be detected.

The reaction can be conducted in a liquid phase in the presence or absence of test molecule, where the reaction products are separated from unreacted components, and the complexes are detected (e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes). Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.

In an alternate embodiment, a homogeneous assay can be utilized. For example, a preformed complex of the target gene product and the interactive cellular or extra-cellular binding partner-product is prepared. One or both of the target molecule or binding partner is labeled, and the signal generated by the label(s) is quenched upon complex formation (e.g., U.S. Pat. No. 4,109,496 that-utilizes this approach for immunoassays). Addition of a test molecule that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target molecule/binding partner complexes can be identified.

Identification of Candidate Therapeutics

Candidate therapeutics for treating colorectal cancer are identified from a group of test molecules that interact with a target molecule. Test molecules are normally ranked according to the degree with which they modulate (e.g., agonize or antagonize) a function associated with the target molecule (e.g., DNA replication and/or processing, RNA transcription and/or processing, polypeptide production and/or processing, and/or biological function/activity), and then top ranking modulators are selected. Also, pharmacogenomic information can determine the rank of a modulator. The top 10% of ranked test molecules often are selected for further testing as candidate therapeutics, and sometimes the top 15%, 20%, or 25% of ranked test molecules are selected for further testing as candidate therapeutics. Candidate therapeutics typically are formulated for administration to a subject.

Therapeutic Formulations

Formulations and pharmaceutical compositions typically include in combination with a pharmaceutically acceptable carrier one or more target molecule modulators. The modulator often is a test molecule identified as having an interaction with a target molecule by a screening method. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner. Also, formulations may include a polypeptide combination with a pharmaceutically acceptable carrier.

A pharmaceutically acceptable carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. See for example, Remington's Pharmaceutical Sciences (2005). Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

A pharmaceutical composition typically is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administrations Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and/or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation often utilized are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Systemic administration might be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. Molecules can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, active molecules are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Each unit containing a predetermined quantity of active compound is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Molecules which exhibit high therapeutic indices often are utilized. While molecules that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such molecules typically lies within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any molecules used in methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC.sub.50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, sometimes about 0.01 to 25 mg/kg body weight, often about 0.1 to 20 mg/kg body weight, and more often about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, sometimes between 2 to 8 weeks, often between about 3 to 7 weeks, and more often for about 4, 5, or 6 weeks. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, can include a series of treatments.

For antibodies, a dosage of 0.1 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg) is often utilized. If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is often appropriate. Generally, partially human antibodies and fully human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosage and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g., into the brain). A method for lipidation of antibodies is described by Cruikshank et al. (Cruikshank et al., 1997).

Antibody conjugates can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.

For compounds, exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight, for example, about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid described herein, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

With regard to nucleic acid formulations, gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (Chen et al., 1994). Pharmaceutical preparations of gene therapy vectors can include a gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells (e.g., retroviral vectors) the pharmaceutical preparation can include one or more cells which produce the gene delivery system. Examples of gene delivery vectors are described herein.

Therapeutic Methods

A therapeutic formulation described above can be administered to a subject in need of a therapeutic for treating colorectal cancer. Therapeutic formulations can be administered by any of the paths described herein. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from pharmacogenomic analyses described herein.

A treatment is the application or administration of a therapeutic formulation to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect colorectal cancer, symptoms of colorectal cancer or a predisposition towards colorectal cancer. A therapeutic formulation includes small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides. Administration of a therapeutic formulation can occur prior to the manifestation of symptoms characteristic of colorectal cancer, such that the cancer is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.

As discussed, successful treatment of colorectal cancer can be brought about by techniques that serve to agonize target molecule expression or function, or alternatively, antagonize target molecule expression or function. These techniques include administration of modulators that include, but are not limited to, small organic or inorganic molecules; antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and FAb, F(ab′)₂ and FAb expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.

Further, antisense and ribozyme molecules that inhibit expression of the target gene can also be used to reduce the level of target gene expression, thus effectively reducing the level of target gene activity. Still further, triple helix molecules can be utilized in reducing the level of target gene activity. Antisense, ribozyme and triple helix molecules are discussed above. It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extra-cellular polypeptide, it can be preferable to co-administer normal target gene polypeptide into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.

Another method by which nucleic acid molecules may be utilized in treating or preventing colorectal cancer is use of aptamer molecules specific for target molecules. Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to ligands (Osborne et al., 1997; Patel, 1997).

Yet another method of utilizing nucleic acid molecules for colorectal cancer treatment is gene therapy, which can also be referred to as allele therapy. The invention thus includes a gene therapy method for treating colorectal cancer in a subject, which includes contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer. The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer SNPs associated with colorectal cancer than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human. Allele therapy methods often are utilized in conjunction with a method of first determining whether a subject has genomic DNA that includes SNPs associated with colorectal cancer.

Another allele therapy is a method which comprises contacting one or more cells in the subject or from the subject with a polypeptide encoded by a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer. The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence includes fewer SNPs associated with colorectal cancer than the second nucleotide sequence. The first nucleotide sequence may include a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is usually a human.

For antibody-based therapies, antibodies can be generated that are both specific for target molecules and that reduce target molecule activity. Such antibodies may be administered in instances where antagonizing a target molecule function is appropriate for the treatment of colorectal cancer.

In circumstances where stimulating antibody production in an animal or a human subject by injection with a target molecule is harmful to the subject, it is possible to generate an immune response against the target molecule by use of anti-idiotypic antibodies (Herlyn and Birebent, 1999; Bhattacharya-Chatterjee and Foon, 1998). Introducing an anti-idiotypic antibody to a mammal or human subject often stimulates production of anti-anti-idiotypic antibodies, which typically are specific to the target molecule. Vaccines directed to colorectal cancer also may be generated in this fashion.

In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies often are utilized. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells. Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen often is utilized. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used. Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (Marasco et al., 1993).

Modulators can be administered to a patient at therapeutically effective doses to treat colorectal cancer. A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of colorectal cancer. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Modulators that exhibit large therapeutic indices often are utilized. While modulators that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such molecules to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds typically lies within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

Another example of effective dose determination for an individual is the ability to directly assay levels of “free” and “bound” compound in the serum of the test subject. Such assays may utilize antibody mimics and/or “biosensors” that have been created through molecular imprinting techniques. Molecules that modulate target molecule activity are used as a template, or “imprinting molecule”, to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated “negative image” of the compound and is able to selectively rebind the molecule under biological assay conditions. A detailed review of this technique can be seen in Ansell et al. (Ansell et al., 1996). Such “imprinted” affinity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrixes in this way can be seen in Vlatakis, et al. (Vlatakis et al., 1993). Through the use of isotope-labeling, the “free” concentration of compound which modulates target molecule expression or activity readily can be monitored and used in calculations of IC₅₀. Such “imprinted” affinity matrixes can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes readily can be assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual IC₅₀.

The examples set forth below are intended to illustrate but not limit the invention.

Genomic DNA samples from patients aged 25-74 and patients with both familial and sporadic CRC with family and unrelated ethnically matched controls were studied. We identified CRC-associated alleles by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2,475 subjects (1,234 cases with colorectal cancer and 1,241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2,194 subjects (1,139 cases with colorectal cancer and 1,055 age matched individuals undiseased at the time of testing). Patients with clinically documented well characterized inherited colorectal cancer syndromes such as Familial Adenomatous Polyposis (FAP) or Hereditary Non Polyposis Colorectal Cancer were excluded from our analysis. Single nucleotide polymorphisms were selected to maximize measurement of genomic variability by choosing these markers that were in the greatest degree of linkage disequilibrium with neighboring SNPs. This was determined by calculating correlation coefficients (r²) with successive neighboring SNPs at each site of polymorphism until an arbitrary cut off of 0.8 was observed. Marker SNPs selected for measurement were in linkage disequilibrium with a maximal number of adjacent SNPs, thus providing an economical method for measuring diversity over a large portion of the genome.

Single Nucleotide Polymorphisms selected for study were derived from the International Haplotype Mapping Project (http://www.hapmap.org) August 2004 release, information about which is available from the National Institutes of Health, National Institutes of Health (NIH; http://www.nih.gov/), 9000 Rockville Pike, Bethesda, Md. 20892. The SNPs were analyzed on DNA from our control and study population using either the Illumina Bead Array system (http://www.illumina.com; Illumina, Inc., 9885 Towne Centre Drive, San Diego, Calif. 92121-1975), the MIP platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, Calif. 95051), the Affymetrix GeneChip® Human Mapping 100K Set platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, Calif. 95051), or the Affymetrix GeneChip® Human Mapping 500K Array Set platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, Calif. 95051). The SNPs for the Illumina Bead Array system were selected on the basis of being associated with genes involved in DNA repair, chromosomal stability or signal transduction and expressed in human colon epithelium. The SNPs for the MIP platform were selected to include most SNPs that would alter the coding sequence of a protein product. The SNPs for the Affymetrix GeneChip® Human Mapping 100K Set platform were selected as to cover the entire genome, but the SNPs were preferentially selected in genic regions present on XbaI or HindIII restriction fragments varying in length from about 250 base pairs to about 2000 base pairs. The SNPs for the Affymetrix GeneChip® Human Mapping 500K Array Set platforms were selected as to cover the entire genome, but the SNPs were preferentially selected in genic regions present on NspI and Styl restriction fragments varying in length from about 200 base pairs to about 1100 base pairs. Data was stored and organized using the Nanuq informatics environment of the McGill University and Genome Quebec Innovation Centre (http://www.genomequebec.mcgill.ca/; McGill University and Genome Quebec Innovation Centre, 740, Docteur Penfield Avenue, Montreal, Quebec H3A 1A4). Allele frequencies found within DNA from patients with colorectal cancer and those without this disease were compared using the univariate Mantel-Haenszel Chi-Square statistic.

The inventors of the present invention have discovered single base pair polymorphisms that are present in a highly significant percentage of the genetic DNA of individuals affected with colorectal cancer while only present in a smaller percentage of individuals who are not known to be affected by the disease.

Example 1

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 20900501 of chromosome 1, found within the EIF4G3 gene, was different from those without colorectal cancer (Table 1). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.008235 based on permutation analysis, and the corresponding recessive odds ratio is 1.353 (Table 1). These data further suggest that this marker, located within the EIF4G3 gene, is associated with colorectal cancer risk and that the C allele at position 20900501 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 1 rs no. 2320590 Chromosome; Position 1; 20900501 Gene Name EIF4G3 SEQ ID NO; Position 1761; 222293 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.07125 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 307 520 173 Recessive 0.008235 1.353 1 C 295 486 221

Table 1A indicates SNPs found to be in strong linkage disequilibrium with rs2320590. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 1A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs951805 0.627 20805662 1 rs710311 0.702 20807307 2 rs12123092 0.697 20812307 3 rs12121807 0.702 20814435 4 rs10916859 0.702 20833262 5 rs7548269 0.627 20834778 6 rs7548649 0.702 20835387 7 rs3736880 0.702 20843033 8 rs651085 0.871 20843089 9 rs651538 0.902 20843172 10 rs589755 0.896 20845152 11 rs1021077 0.702 20851322 12 rs12123093 0.603 20859722 13 rs3856173 0.676 20860139 14 rs4233274 0.966 20866984 15 rs1152999 0.57 20868329 16 rs1152998 0.752 20869596 17 rs3125161 0.729 20871652 18 rs3121071 0.551 20873726 19 rs7520481 0.724 20885691 20 rs935918 0.649 20890966 21 rs10753507 0.867 20897686 22 rs4654873 0.603 20897690 23 rs10799665 0.676 20897946 24 rs2320590 — 20900501 25 rs4654874 0.933 20901973 26 rs11805169 0.697 20902168 27 rs4654875 0.555 20910482 28 rs935917 0.729 20912408 29 rs4654724 0.651 20922516 30 rs2305463 0.868 20925487 31 rs7543140 0.605 20925556 32 rs1530946 0.651 20927846 33 rs4654880 0.745 20931914 34 rs10916885 0.925 20934009 35 rs6695218 0.539 20935818 36 rs7519685 0.651 20937929 37 rs2167811 0.646 20939816 38 rs3890762 0.899 20943571 39 rs10737452 0.651 20945070 40 rs10916891 0.551 20945280 41 rs4654725 0.651 20945717 42 rs4654726 0.729 20949204 43 rs17449966 0.629 20949302 44 rs7545133 0.729 20951449 45 rs4654881 0.934 20955075 46 rs2290381 0.651 20958577 47 rs4654883 0.895 20959014 48 rs4654727 0.729 20960041 49 rs2275468 0.729 20965681 50 rs6704421 0.902 20965980 51 rs17410008 0.651 20966007 52 rs4654729 0.934 20969559 53 rs3767247 0.651 20972644 54 rs4654887 0.729 20980229 55 rs10916900 0.934 20984365 56 rs6699704 0.551 20986738 57 rs10916903 0.651 20993250 58 rs11805006 0.934 20994909 59 rs6692677 0.934 20997023 60 rs17450586 0.565 20999899 61 rs12407731 0.934 21000095 62 rs10916906 0.643 21000981 63 rs6698440 0.9 21004018 64 rs10916907 0.9 21006394 65 rs10442633 0.9 21010403 66 rs12133780 0.694 21016114 67 rs3767248 0.694 21022160 68 rs6700459 0.617 21024702 69 rs12137408 0.9 21028251 70 rs6697555 0.694 21033244 71 rs10916911 0.9 21035367 72 rs6669077 0.894 21035826 73 rs6697284 0.9 21040905 74 rs2271115 0.694 21041170 75 rs6700718 0.687 21044669 76 rs4654893 0.551 21050902 77 rs12021529 0.551 21051467 78 rs7540023 0.571 21055398 79 rs10916919 0.566 21062830 80 rs10799677 0.517 21063762 81 rs10799678 0.9 21068091 82 rs12123300 0.575 21068874 83 rs2874367 0.9 21069797 84 rs11302414 0.664 21072609 85 rs12130664 0.617 21078118 86 rs6661116 0.694 21082461 87 rs12070677 0.898 21082628 88 rs6681064 0.694 21084950 89 rs6659152 0.662 21101147 90 rs6426658 0.617 21106482 91 rs6685914 0.545 21107684 92 rs6684976 0.694 21112807 93 rs6668370 0.9 21114874 94 rs6703227 0.694 21120116 95 rs964466 0.565 21120469 96 rs10493006 0.617 21121210 97 rs6426665 0.9 21127511 98 rs10916927 0.617 21131101 99 rs6658526 0.541 21136620 100 rs1354792 0.9 21137181 101 rs12567861 0.551 21140439 102 rs10916930 0.559 21140663 103 rs6426667 0.897 21141522 104 rs6426668 0.694 21141902 105 rs6692244 0.694 21142192 106 rs7521711 0.9 21145524 107 rs1567128 0.512 21149959 108

Example 2

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 54538208 of chromosome 1, found within the SSBP3 gene, was different from those without colorectal cancer (Table 2). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.002647, and the corresponding dominant odds ratio is 1.348 (Table 2). These data further suggest that this marker, located within the SSBP3 gene, is associated with colorectal cancer risk and that the C allele at position 54538208 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 2 rs no. 10489565 Chromosome; Position 1; 54538208 Gene Name SSBP3 SEQ ID NO; Position 1762; 45710 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.89558 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 C 740 240 20 Dominant 0.002647 1.348 1 C 680 295 27

Table 2A indicates SNPs found to be in strong linkage disequilibrium with rs10489565. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 2A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs4601533 0.929 54531998 109 rs10489565 — 54538208 110 rs12024740 0.586 54548927 111 rs2073108 0.656 54551090 112 rs17101278 0.656 54552517 113 rs12029610 0.639 54556623 114 rs3795357 0.656 54557621 115 rs12022116 0.635 54561302 116 rs12043222 0.656 54561394 117 rs2297573 0.656 54562638 118 rs4141420 0.591 54563585 119 rs12045400 0.656 54563831 120

Example 3

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 97159204 of chromosome 1 was different from those without colorectal cancer (Table 3). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.004716, and the corresponding dominant odds ratio is 1.428 (Table 3). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 97159204 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 3 rs no. 10493889 Chromosome; Position 1; 97159204 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.80154 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 C 841 124 5 Dominant 0.004716 1.428 1 C 817 173 6

Table 3A indicates SNPs found to be in strong linkage disequilibrium with rs10493889. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 3A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs17525524 0.667 96911594 121 rs2391782 0.667 96938696 122 rs17115733 0.647 96961817 123 rs12024594 0.73 97005044 124 rs11165746 1.0 97141267 125 rs10493889 — 97159204 126

Example 4

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 97657313 of chromosome 1, found within the DPYD gene, was different from those without colorectal cancer (Table 4). The dominant test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.047614, and the corresponding dominant odds ratio is 1.236 (Table 4). These data further suggest that this marker, located within the DPYD gene, is associated with colorectal cancer risk and that the A allele at position 97657313 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 4 rs no. 945881 Chromosome; Position 1; 97657313 Gene Name DPYD SEQ ID NO; Position 1763; 441288 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.17718 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 236 569 403 Dominant 0.047614 1.236 1 A 202 609 419

Table 4A indicates SNPs found to be in strong linkage disequilibrium with rs945881. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 4A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs11165879 0.699 97653506 127 rs945881 — 97657313 128 rs11165881 1.0 97659904 129

Example 5

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 107056364 of chromosome 1 was different from those without colorectal cancer (Table 5). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.0856 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.171 (Table 5). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 107056364 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 5 rs no. 2049064 Chromosome; Position 1; 107056364 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.77232 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 761 222 14 Trend 0.0856 1.171 1 A 729 247 20

Table 5A indicates SNPs found to be in strong linkage disequilibrium with rs2049064. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 5A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs11184922 0.502 106818235 130 rs7530540 0.61 106828844 131 rs4914979 0.61 106830088 132 rs4409683 0.631 106833215 133 rs10430081 0.568 106891798 134 rs7527883 0.688 106912949 135 rs12066688 0.688 106928115 136 rs7545951 0.574 106930964 137 rs4311915 0.688 106937218 138 rs17017475 0.688 106971827 139 rs17017532 0.935 106998017 140 rs17017567 0.932 107004258 141 rs12085613 0.932 107006719 142 rs12078403 0.935 107010986 143 rs12409858 0.935 107011275 144 rs11184981 0.873 107011305 145 rs12407314 0.935 107011409 146 rs12406199 0.932 107011554 147 rs12407335 0.935 107011627 148 rs12410591 0.932 107012941 149 rs10494050 0.935 107014445 150 rs12079669 0.928 107017707 151 rs10494052 0.935 107021830 152 rs17017658 0.935 107024684 153 rs17492154 0.63 107025142 154 rs2139462 0.935 107033827 155 rs17017694 0.932 107034845 156 rs17017723 1.0 107044596 157 rs17017736 1.0 107047341 158 rs12097821 1.0 107048343 159 rs955988 1.0 107052637 160 rs1519889 1.0 107054139 161 rs1519887 1.0 107056341 162 rs2049064 — 107056364 163 rs1607634 0.734 107079348 164 rs1519874 0.688 107080550 165 rs2030341 0.688 107081508 166 rs908953 0.734 107086826 167 rs10881449 0.688 107088101 168 rs1607635 0.63 107091984 169 rs1156426 0.688 107092704 170 rs7530116 0.688 107093768 171 rs12094371 0.688 107095587 172 rs1519875 0.688 107096669 173 rs1519876 0.672 107098220 174 rs10881450 0.688 107100885 175 rs2102909 0.688 107103052 176 rs7511900 0.688 107112872 177 rs10465780 0.672 107115313 178 rs11184996 0.688 107115334 179

Example 6

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 114975727 of chromosome 1, found within the D1S155E gene, was different from those without colorectal cancer (Table 6). The dominant test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.002032, and the corresponding dominant odds ratio is 1.638 (Table 6). These data further suggest that this marker, located within the D1S155E gene, is associated with colorectal cancer risk and that the G allele at position 114975727 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 6 rs no. 10489525 Chromosome; Position 1; 114975727 Gene Name D1S155E SEQ ID NO; Position 1764; 36894 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.04271 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 107 388 476 Dominant 0.002032 1.638 1 G  70 394 532

Table 6A indicates SNPs found to be in strong linkage disequilibrium with rs10489525. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 6A Linked SNPs SNP r² Position on chr1 SEQ ID NO rs10489525 — 114975727 183

Example 7

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 115166656 of chromosome 1, found within the SYCP1 gene, was different from those without colorectal cancer (Table 7). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.002586 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.187 (Table 7). These data further suggest that this marker, located within the SYCP1 gene, is associated with colorectal cancer risk and that the A allele at position 115166656 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 7 rs no. 360659 Chromosome; Position 1; 115166656 Gene Name SYCP1 SEQ ID NO; Position 1765; 57160 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.43217 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 414 552 202 Trend 0.002586 1.187 1 A 378 575 264

Table 7A indicates SNPs found to be in strong linkage disequilibrium with rs360659. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 7A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs2010899 0.518 114947052 180 rs969273 0.522 114968711 181 rs6671984 0.522 114969563 182 rs2007231 0.522 114978348 184 rs2144428 0.569 114981253 185 rs6663115 0.522 114984296 186 rs4140445 0.522 115004020 187 rs3121503 0.966 115071842 188 rs1286555 0.542 115073938 189 rs3121506 0.599 115075249 190 rs3121507 0.964 115077252 191 rs6689326 0.583 115081154 192 rs3126216 0.966 115084567 193 rs1286560 0.583 115087972 194 rs869990 0.583 115091656 195 rs360599 0.815 115100040 196 rs360603 0.966 115101751 197 rs360606 0.583 115103811 198 rs360607 0.599 115104443 199 rs360614 1.0 115111982 200 rs360617 0.603 115116141 201 rs360622 1.0 115119103 202 rs360627 1.0 115125087 203 rs360630 0.564 115127174 204 rs360634 1.0 115132157 205 rs360635 0.564 115132560 206 rs360636 1.0 115132947 207 rs360643 1.0 115139005 208 rs360645 0.564 115139260 209 rs360647 1.0 115141772 210 rs360655 0.564 115159909 211 rs360659 — 115166656 212 rs360661 0.62 115167322 213 rs360576 0.546 115171216 214 rs360586 0.564 115179531 215 rs360588 1.0 115180386 216 rs360590 0.504 115182953 217 rs360591 0.809 115183282 218 rs360596 0.815 115185601 219 rs360668 0.815 115193640 220 rs506934 0.51 115200356 221 rs360675 0.583 115202960 222 rs360682 0.815 115209101 223 rs12135023 0.815 115217819 224 rs1591899 0.805 115226640 225 rs12125190 0.815 115234779 226 rs12026343 0.815 115236258 227 rs7416955 0.812 115242333 228 rs4839017 0.815 115242502 229 rs11102859 0.806 115242740 230 rs6698174 0.815 115244057 231 rs7536888 0.815 115261728 232 rs4839399 0.815 115268188 233 rs11102872 0.815 115277042 234 rs7515454 0.815 115278233 235 rs7517739 0.815 115278345 236 rs7541251 0.815 115278448 237 rs6537849 0.815 115278686 238 rs1575070 0.674 115279927 239 rs1575069 0.689 115280070 240 rs12136420 0.689 115281663 241 rs7530810 0.689 115282510 242 rs7523360 0.689 115282884 243 rs1321108 0.689 115284407 244 rs11102874 0.749 115285912 245 rs3754363 0.686 115287160 246 rs1321107 0.583 115287345 247 rs7514765 0.612 115289952 248 rs1998008 0.703 115292582 249 rs4611011 0.633 115298443 250 rs7413646 0.638 115298798 251 rs11102878 0.55 115303040 252

Example 8

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 143040559 of chromosome 1, found within the FLJ25124 gene, was different from those without colorectal cancer (Table 8). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.000396 based on permutation analysis, and the corresponding recessive odds ratio is 1.653 (Table 8). These data further suggest that this marker, located within the FLJ25124 gene, is associated with colorectal cancer risk and that the G allele at position 143040559 of chromosome 1 is associated with an increased risk of developing colorectal cancer.

TABLE 8 rs no. 10494240 Chromosome; Position 1; 143040559 Gene Name FLJ25124 SEQ ID NO; Position 1766; 2272 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.10646 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 433 447  90 Recessive 0.000396 1.653 1 G 433 419 144

Table 8A indicates SNPs found to be in strong linkage disequilibrium with rs10494240. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 8A Linked SNPs Position SNP r² on chr1 SEQ ID NO rs4636400 0.611 142933600 253 rs6688400 0.71 142994415 254 rs872786 0.71 142996870 255 rs2274617 0.898 143024965 256 rs12410298 0.501 143037007 257 rs720899 1.0 143039966 258 rs10494240 — 143040559 259 rs12125340 0.965 143043494 260

Example 9

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 20254115 of chromosome 2 was different from those without colorectal cancer (Table 9). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.028471, and the corresponding dominant odds ratio is 1.265 (Table 9). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 20254115 of chromosome 2 is associated with an increased risk of developing colorectal cancer.

TABLE 9 rs no. 973128 Chromosome; Position 2; 20254115 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.56307 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 249 475 245 Dominant 0.028471 1.265 1 C 213 513 266

Table 9A indicates SNPs found to be in strong linkage disequilibrium with rs973128. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 9A Linked SNPs Position SNP r² on chr2 SEQ ID NO rs17697743 0.755 20250764 261 rs6753830 1.0 20250981 262 rs975951 1.0 20252966 263 rs973128 — 20254115 264 rs875411 1.0 20254650 265 rs875412 1.0 20255588 266 rs6744463 1.0 20256013 267 rs2881879 0.534 20257476 268 rs4666362 0.522 20258973 269 rs6531212 0.522 20259648 270 rs46663641 0.513 20260227 271

Example 10

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 49189474 of chromosome 2, found within the FSHR gene, was different from those without colorectal cancer (Table 10). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.005443 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.193 (Table 10). These data further suggest that this marker, located within the FSHR gene, is associated with colorectal cancer risk and that the G allele at position 49189474 of chromosome 2 is associated with an increased risk of developing colorectal cancer.

TABLE 10 rs no. 1504175 Chromosome; Position 2; 49189474 Gene Name FSHR SEQ ID NO; Position 1767; 103808 Genotype; Phenotype n = G; increased risk Hard-Weinberg 0.43804 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 G 323 501 175 Trend 0.005443 1.193 1 G 281 498 220

Table 10A indicates SNPs found to be in strong linkage disequilibrium with rs1504175. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 10A Linked SNPs Position SNP r² on chr2 SEQ ID NO rs3788981 0.506 49157212 272 rs9807991 0.693 49163446 273 rs10171892 0.579 49169518 274 rs10865238 0.626 49180455 275 rs12614817 0.776 49183068 276 rs3850344 0.731 49184463 277 rs6716567 1.0 49185265 278 rs11125197 1.0 49186995 279 rs13004879 0.688 49187513 280 rs3913665 0.757 49187893 281 rs1504175 — 49189474 282 rs1504177 0.737 49189694 283 rs2134811 0.757 49190619 284 rs13032266 1.0 49191171 285 rs1504188 0.74 49191484 286 rs1504190 0.737 49192006 287 rs2091786 0.565 49195881 288 rs1394207 0.572 49199434 289 rs4420736 0.565 49199611 290 rs11686474 0.565 49199634 291 rs11680730 0.565 49199711 292 rs11676909 0.581 49203878 293 rs12473815 0.579 49204013 294 rs11125206 0.598 49204336 295 rs1882560 0.565 49205020 296 rs12620805 0.598 49205539 297 rs11903014 0.786 49205989 298 rs6716923 0.552 49227109 299 rs976230 0.552 49239677 300 rs11898430 0.539 49239769 301 rs974896 0.568 49242500 302 rs974897 0.552 49242583 303 rs4510264 0.552 49244528 304 rs9309159 0.502 49253703 305 rs1032838 0.556 49311997 306 rs11125217 0.556 49319087 307 rs11685850 0.556 49329514 308 rs9309160 0.556 49329682 309 rs6720857 0.506 49332061 310 rs4564810 0.53 49332761 311 rs11125222 0.524 49335916 312

Example 11

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 186869364 of chromosome 2 was different from those without colorectal cancer (Table 11). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.002126 based on permutation analysis, and the corresponding recessive odds ratio is 3.892 (Table 11). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 186869364 of chromosome 2 is associated with an increased risk of developing colorectal cancer.

TABLE 11 rs no. 10497667 Chromosome; Position 2; 186869364 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.12585 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 G 797 197 6 Recessive 0.002126 3.892 1 G 791 188 23

Table 11A indicates SNPs found to be in strong linkage disequilibrium with rs10497667. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 11A Linked SNPs Position SNP r² on chr2 SEQ ID NO rs7582258 0.611 186729521 313 rs12615770 0.611 186748482 314 rs12998383 0.635 186752544 315 rs16827480 0.63 186753368 316 rs12614513 0.726 186759677 317 rs10931222 0.63 186771130 318 rs991084 0.63 186774634 319 rs13005466 0.63 186783677 320 rs6750636 0.61 186788675 321 rs13003934 0.612 186795981 322 rs12999989 0.629 186797056 323 rs13028175 0.59 186797101 324 rs12999474 0.627 186804008 325 rs12373738 0.63 186822924 326 rs10186498 0.63 186841731 327 rs6725283 0.891 186849447 328 rs13419562 0.63 186854278 329 rs13394207 0.63 186854406 330 rs13421172 0.63 186856196 331 rs4284795 1.0 186866149 332 rs2887816 0.63 186869233 333 rs10497667 — 186869364 334 rs13388196 0.629 186870116 335 rs2370681 0.63 186873391 336 rs12233005 0.63 186873805 337 rs8179713 1.0 186874321 338 rs13416578 0.63 186876760 339 rs12614595 1.0 186877596 340 rs2370677 1.0 186878043 341 rs4500906 0.908 186883056 342 rs16827554 1.0 186887466 343 rs2370672 1.0 186891840 344 rs2370671 1.0 186892009 345 rs7584724 1.0 186895423 346 rs4461230 1.0 186897281 347 rs16827602 1.0 186898014 348 rs6434164 1.0 186899824 349 rs2370670 1.0 186903194 350 rs16827614 1.0 186905158 351 rs3107174 0.915 186910195 352 rs3107423 0.908 186918596 353 rs2887818 0.915 186918660 354 rs3112312 0.901 186933341 355 rs1878754 0.915 186935034 356 rs3112315 0.915 186937617 357 rs2370659 0.915 186938372 358 rs3112316 0.915 186938761 359 rs3107410 0.915 186940537 360 rs3112317 0.915 186942136 361 rs10195099 0.591 186944471 362 rs2370662 0.915 186945120 363 rs10931232 0.915 186950816 364 rs2029085 0.915 187032899 365 rs10497669 0.643 187050892 366

Example 12

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 218776751 of chromosome 2, found within the FLJ46536 gene, was different from those without colorectal cancer (Table 12). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.005832 based on permutation analysis, and the corresponding recessive odds ratio is 1.335 (Table 12). These data further suggest that this marker, located within the FLJ46536 gene, is associated with colorectal cancer risk and that the C allele at position 218776751 of chromosome 2 is associated with an increased risk of developing colorectal cancer.

TABLE 12 rs no. 4133195 Chromosome; Position 2; 218776751 Gene Name FLJ46536 SEQ ID NO; Position 1768; 51535 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.79932 Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 288 493 219 Recessive 0.005832 1.335 1 C 279 450 273

Table 12A indicates SNPs found to be in strong linkage disequilibrium with rs4133195. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 12A Linked SNPs Position SNP r² on chr2 SEQ ID NO rs4672870 0.647 218767422 367 rs12694425 0.647 218767819 368 rs12694426 0.637 218767857 369 rs10932745 0.669 218768482 370 rs11687200 0.665 218770121 371 rs11676275 0.669 218770314 372 rs12694427 0.669 218770551 373 rs6737563 0.934 218771180 374 rs13013361 0.933 218773021 375 rs4133195 — 218776751 376 rs6726126 1.0 218777739 377 rs10804264 0.819 218781315 378 rs12694428 0.63 218784326 379 rs13035513 0.935 218786186 380 rs13007992 0.792 218789557 381 rs7426289 0.935 218791821 382 rs6436029 0.785 218803037 383 rs4674257 0.935 218814280 384 rs4674259 0.935 218816511 385 rs6723449 0.934 218823086 386 rs1126579 0.967 218826240 387 rs4674261 0.625 218830515 388 rs11677534 0.935 218832566 389 rs13009946 0.935 218833258 390 rs7594532 0.918 218833506 391 rs7607437 0.935 218833898 392 rs11676348 0.74 218835652 393 rs13027120 0.935 218846420 394 rs1008563 0.625 218852394 395 rs1008562 0.935 218852478 396 rs4674267 0.625 218871943 397 rs13397673 0.641 218873288 398

Example 13

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 230825727 of chromosome 2 was different from those without colorectal cancer (Table 13). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.022599 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.160 (Table 13). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 230825727 of chromosome 2 is associated with an increased risk of developing colorectal cancer.

TABLE 13 rs no. 10498243 Chromosome; Position 2; 230825727 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.12363 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 467 424 75 Trend 0.022599 1.160 1 C 444 443 107

Table 13A indicates SNPs found to be in strong linkage disequilibrium with rs10498243. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 13A Linked SNPs Position SNP r² on chr2 SEQ ID NO rs12694839 0.527 230822818 399 rs12694840 0.523 230822908 400 rs6706782 1.0 230823742 401 rs6707129 1.0 230824051 402 rs10933323 1.0 230824308 403 rs10933324 1.0 230824428 404 rs1529377 1.0 230825316 405 rs12694841 1.0 230825613 406 rs10498243 — 230825727 407 rs6715536 1.0 230825877 408 rs1549567 1.0 230827852 409 rs6721137 1.0 230828862 410 rs1365775 1.0 230829298 411 rs10933326 1.0 230830081 412 rs2396713 0.961 230830316 413 rs13004807 1.0 230830886 414 rs10048686 1.0 230832540 415 rs2894694 0.501 230838320 416 rs11677105 0.527 230842525 417

Example 14

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 25062781 of chromosome 3 was different from those without colorectal cancer (Table 14). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.009697 based on permutation analysis, and the corresponding recessive odds ratio is 1.298 (Table 14). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 25062781 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 14 rs no. 4484159 Chromosome; Position 3; 25062781 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.29815 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 22 278 667 Recessive 0.009697 1.298 1 A 22 231 730

Table 14A indicates SNPs found to be in strong linkage disequilibrium with rs4484159. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 14A Linked SNPs Position SNP r² on chr3 SEQ ID NO rs13067187 0.583 25052936 418 rs6777624 0.854 25054402 419 rs9866836 0.877 25056885 420 rs17015670 1.0 25061156 421 rs4484159 — 25062781 422 rs1604007 0.817 25068060 423 rs988268 0.808 25076452 424 rs6550943 0.778 25084253 425 rs6777955 0.932 25084806 426 rs6766372 0.757 25086476 427 rs994267 0.825 25090198 428 rs1574901 0.825 25090417 429 rs6775433 0.824 25091862 430 rs4858698 0.825 25093457 431 rs7430038 0.825 25099388 432 rs1587430 0.825 25100369 433 rs4858700 0.517 25102693 434 rs11294076 0.788 25105990 435 rs4858703 0.825 25108277 436 rs2036270 0.825 25112900 437 rs972016 0.825 25114656 438 rs1603987 0.825 25115540 439 rs6807196 0.696 25117575 440 rs4858704 0.517 25118394 441 rs1580817 0.825 25121605 442

Example 15

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 25244762 of chromosome 3, found within the LOC442077 gene, was different from those without colorectal cancer (Table 15). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.005641 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.300 (Table 15). These data further suggest that this marker, located within the LOC442077 gene, is associated with colorectal cancer risk and that the A allele at position 25244762 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 15 rs no. 10510558 Chromosome; Position 3; 25244762 Gene Name LOC442077 SEQ ID NO; Position 1769; 53870 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.80066 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 20 253 724 Trend 0.005641 1.300 1 A 13 209 779

Table 15A indicates SNPs found to be in strong linkage disequilibrium with rs10510558. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 15A Linked SNPs Position SNP r² on chr3 SEQ ID NO rs13060347 0.929 25169305 443 rs17517792 0.929 25170688 444 rs17517931 0.914 25184366 445 rs13068891 0.853 25188663 446 rs13061437 0.924 25194200 447 rs17578042 0.929 25205423 448 rs17578259 0.929 25207827 449 rs13100362 0.872 25211158 450 rs2068130 0.818 25211837 451 rs1561115 0.932 25235457 452 rs17015971 0.932 25238040 453 rs13096074 0.844 25239011 454 rs17015978 1.0 25239845 455 rs7432016 1.0 25243914 456 rs10510558 — 25244762 457 rs10510559 1.0 25244932 458 rs10510560 1.0 25245547 459 rs13092896 0.799 25250478 460 rs7427426 1.0 25264520 461 rs1601161 1.0 25265009 462 rs1992060 0.919 25269521 463 rs1992059 0.932 25273091 464 rs13082318 0.932 25273425 465 rs13087573 0.932 25274083 466 rs17016060 0.932 25275052 467 rs13074533 0.932 25277488 468 rs10510561 0.932 25279386 469 rs17016078 0.932 25280012 470 rs13093059 0.932 25280571 471 rs13068143 0.932 25283486 472 rs13091754 0.932 25283965 473 rs17016117 0.932 25284812 474 rs17016120 0.932 25285067 475 rs13059799 0.932 25287098 476 rs13082440 0.928 25287161 477 rs17016133 0.932 25288171 478 rs13084418 0.932 25291318 479 rs13084608 0.932 25291410 480 rs17016141 0.861 25295964 481 rs1436239 0.861 25300483 482

Example 16

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 62952892 of chromosome 3 was different from those without colorectal cancer (Table 16). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.001158 based on permutation analysis, and the corresponding recessive odds ratio is 2.127 (Table 16). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 62952892 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 16 rs no. 4404442 Chromosome; Position 3; 62952892 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.06369 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 C 623 321 27 Recessive 0.001158 2.127 1 C 627 310 57

Table 16A indicates SNPs found to be in strong linkage disequilibrium with rs4404442. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 16A Linked SNPs Position SNP r² on chr3 SEQ ID NO rs9828340 0.528 62937809 483 rs12631618 1.0 62941462 484 rs6807315 1.0 62943033 485 rs4312654 1.0 62943151 486 rs4583651 1.0 62943547 487 rs13072243 1.0 62945427 488 rs4613448 0.948 62949979 489 rs4404442 — 62952892 490 rs13091015 1.0 62955440 491 rs9814898 1.0 62957942 492 rs17067503 1.0 62958060 493 rs10510890 0.948 62959133 494 rs9821058 1.0 62959399 495 rs10510891 1.0 62960430 496 rs13084396 1.0 62961266 497 rs4147406 0.95 62962215 498 rs2367590 1.0 62964393 499 rs17067527 0.898 62965607 500 rs12488885 0.948 62966446 501 rs17361212 0.752 62966549 502 rs11130909 0.947 62968123 503 rs13099709 0.948 62968779 504 rs13079904 0.948 62968976 505 rs2367591 0.898 62969677 506 rs9850740 0.947 62970029 507 rs10510892 0.948 62970190 508 rs2367592 0.852 62970589 509 rs11130910 0.887 62971291 510 rs7372226 0.947 62972138 511 rs13061838 0.898 62975188 512 rs6770985 0.528 62981633 513 rs1447443 0.528 62982901 514 rs12637433 0.528 62983787 515 rs4688357 0.555 62985367 516

Example 17

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 120037273 of chromosome 3 was different from those without colorectal cancer (Table 17). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.000464 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.407 (Table 17). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 120037273 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 17 rs no. 1402582 Chromosome; Position 3; 120037273 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.00386 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 776 202 3 Trend 0.000464 1.407 1 A 710 254 11

Table 17A indicates SNPs found to be in strong linkage disequilibrium with rs1402582. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 17A Linked SNPs SNP r² Position on chr3 SEQ ID NO rs1081903 0.549 120036240 519 rs1402582 — 120037273 520 rs812824 0.608 120037336 521 rs2936727 0.608 120037804 522 rs1521289 0.608 120039183 523 rs2684320 0.608 120039851 524 rs2649882 0.608 120044441 525

Example 18

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 120037336 of chromosome 3 was different from those without colorectal cancer (Table 18). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.001767 based on permutation analysis, and the corresponding recessive odds ratio is 1.986 (Table 18). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 120037336 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 18 rs no. 812824 Chromosome; Position 3; 120037336 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.01053 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 G 582 357 32 Recessive 0.001767 1.986 1 G 575 356 63

Table 18A indicates SNPs found to be in strong linkage disequilibrium with rs812824. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 18A Linked SNPs SNP r² Position on chr3 SEQ ID NO rs881603 0.705 120013362 517 rs881604 0.711 120013382 518 rs1081903 0.953 120036240 519 rs1402582 0.608 120037273 520 rs812824 — 120037336 521 rs2936727 1.0 120037804 522 rs1521289 1.0 120039183 523 rs2684320 1.0 120039851 524 rs2649882 1.0 120044441 525

Example 19

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 186033203 of chromosome 3, found within the KIAA0804 gene, was different from those without colorectal cancer (Table 19). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.009969 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.193 (Table 19). These data further suggest that this marker, located within the KIAA0804 gene, is associated with colorectal cancer risk and that the A allele at position 186033203 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 19 rs no. 9830734 Chromosome; Position 3; 186033203 Gene Name KIAA0804 SEQ ID NO; Position 1770; 8081 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.08380 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 98 512 520 Trend 0.009969 1.193 1 A 81 472 583

Table 19A indicates SNPs found to be in strong linkage disequilibrium with rs9830734. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 19A Linked SNPs Position SNP r² on chr3 SEQ ID NO rs4686769 0.765 186008653 526 rs2377115 0.71 186008673 527 rs725656 0.636 186008910 528 rs7640976 1.0 186012692 529 rs13079793 0.619 186027445 530 rs10513799 0.636 186032241 531 rs9830734 — 186033203 532 rs4432622 0.617 186038166 533 rs11710551 0.643 186041770 534 rs16859344 0.636 186043671 535 rs2305240 0.636 186049741 536 rs11720538 0.623 186052729 537 rs6443999 0.6 186056257 538 rs16859357 0.593 186058136 539 rs724273 0.597 186058533 540 rs6809079 0.597 186059022 541 rs7340698 0.636 186060619 542 rs3733165 0.553 186063619 543 rs2377107 0.593 186070576 544 rs7619460 0.597 186070838 545 rs9757458 0.615 186072802 546 rs7628188 0.553 186073295 547 rs7638317 0.557 186076934 548 rs11717139 0.593 186079782 549 rs11714752 0.588 186081364 550 rs9881074 0.593 186083378 551 rs1000270 0.593 186090182 552 rs6762984 0.529 186099834 553 rs4324453 0.593 186104572 554 rs7618180 0.557 186112996 555 rs9821657 0.557 186113805 556 rs4686879 0.556 186115949 557 rs7611263 0.597 186117351 558 rs9825856 0.604 186119962 559 rs9290804 0.557 186126928 560 rs10446349 0.597 186131728 561 rs13066369 0.518 186142625 562 rs9870352 0.576 186146360 563 rs4422281 0.518 186148006 564 rs9820111 0.518 186149057 565 rs6784179 0.518 186152026 566 rs7623170 0.512 186156901 567 rs6765821 0.524 186244971 568 rs6783157 0.521 186252104 569 rs12636670 0.526 186267820 570

Example 20

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 187873329 of chromosome 3, found within the HRG gene, was different from those without colorectal cancer (Table 20). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.003172, and the corresponding dominant odds ratio is 1.456 (Table 20). These data further suggest that this marker, located within the HRG gene, is associated with colorectal cancer risk and that the C allele at position 187873329 of chromosome 3 is associated with an increased risk of developing colorectal cancer.

TABLE 20 rs no. 9898 Chromosome; Position 3; 187873329 Gene Name HRG SEQ ID NO; Position 1771; 6830 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.00984 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 167 481 483 Dominant 0.003172 1.456 1 C 121 514 503

Table 20A indicates SNPs found to be in strong linkage disequilibrium with rs9898. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 20A Linked SNPs Position SNP r² on chr3 SEQ ID NO rs3733159 0.8 187843111 571 rs1868154 0.574 187857373 572 rs11720187 0.654 187860431 573 rs9898 — 187873329 574 rs1042464 0.547 187878274 575

Example 21

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 4862109 of chromosome 4 was different from those without colorectal cancer (Table 21). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.000489 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.464 (Table 21). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 4862109 of chromosome 4 is associated with an increased risk of developing colorectal cancer.

TABLE 21 rs no. 10516168 Chromosome; Position 4; 4862109 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.83766 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 837 157 6 Trend 0.000489 1.464 1 A 776 215 10

Table 21A indicates SNPs found to be in strong linkage disequilibrium with rs10516168. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 21A Linked SNPs Position SNP r² on chr4 SEQ ID NO rs6814552 0.667 4846426 576 rs2089781 1.0 4857130 577 rs13149006 0.848 4857759 578 rs10516168 — 4862109 579 rs767564 0.79 4867970 580

Example 22

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 73418955 of chromosome 4 was different from those without colorectal cancer (Table 22). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.003466 based on permutation analysis, and the corresponding recessive odds ratio is 1.478 (Table 22). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 73418955 of chromosome 4 is associated with an increased risk of developing colorectal cancer.

TABLE 22 rs no. 10518098 Chromosome; Position 4; 73418955 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.20305 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 G 404 459 108 Recessive 0.003466 1.478 1 G 401 437 155

Table 22A indicates SNPs found to be in strong linkage disequilibrium with rs10518098. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 22A Linked SNPs Position SNP r² on chr4 SEQ ID NO rs11726886 0.533 73187634 581 rs10518093 0.621 73200067 582 rs4129733 0.749 73328055 583 rs4337703 0.749 73346262 584 rs11733404 0.73 73346848 585 rs11737827 0.749 73348223 586 rs12651098 0.738 73357454 587 rs11734943 0.675 73363372 588 rs9790741 0.676 73365920 589 rs11940196 0.925 73368604 590 rs10755169 0.963 73376981 591 rs11729989 0.884 73386336 592 rs4333153 0.963 73387894 593 rs17775363 0.888 73401936 594 rs17718934 0.889 73402263 595 rs885521 0.889 73403367 596 rs2137735 0.889 73409745 597 rs7675397 1.0 73418036 598 rs10518098 — 73418955 599 rs1554016 1.0 73419931 600 rs10938007 0.91 73420592 601 rs4444797 1.0 73420874 602 rs4502651 1.0 73420904 603 rs4301078 1.0 73420954 604 rs7700096 1.0 73421198 605 rs7654146 1.0 73421361 606 rs2056022 1.0 73421626 607 rs2056023 1.0 73421636 608 rs2365795 1.0 73424191 609 rs6840004 0.926 73426574 610 rs1121770 1.0 73428206 611 rs11940139 1.0 73428609 612 rs868028 1.0 73429022 613 rs868026 1.0 73429166 614 rs7673208 1.0 73429961 615 rs4694467 1.0 73430864 616 rs4694468 0.924 73432371 617 rs1398982 1.0 73432662 618 rs10938009 0.926 73433172 619 rs996154 1.0 73435810 620 rs996153 1.0 73435851 621 rs2365797 1.0 73437550 622 rs1018283 1.0 73437882 623 rs10805048 0.926 73438096 624 rs957047 1.0 73440758 625 rs957046 1.0 73441001 626 rs957045 1.0 73441029 627 rs10008822 1.0 73442206 628 rs4547769 1.0 73445194 629 rs7674709 0.835 73446950 630 rs10938010 0.888 73448534 631 rs4694469 0.926 73451047 632 rs7662481 1.0 73453617 633 rs884511 0.89 73454336 634 rs9685357 1.0 73455010 635 rs10029245 0.924 73456969 636 rs10938012 0.925 73461427 637 rs4694120 0.926 73468266 638 rs10518099 0.926 73468802 639 rs10518100 0.89 73469693 640 rs9985540 0.889 73472897 641 rs985302 0.921 73473510 642 rs2117380 0.855 73474331 643 rs1865383 0.816 73475459 644 rs984406 0.842 73476824 645 rs2175830 0.603 73481968 646 rs1554017 0.603 73482388 647 rs10006866 0.603 73484550 648 rs1513894 0.661 73489468 649 rs11729217 0.593 73491229 650 rs6857543 0.662 73491598 651 rs1398980 0.574 73492707 652 rs7681169 0.574 73493192 653 rs10433664 0.574 73493907 654 rs10050160 0.574 73496343 655 rs6446823 0.662 73496916 656 rs7679388 0.574 73501955 657

Example 23

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 156010845 of chromosome 4 was different from those without colorectal cancer (Table 23). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.011861, and the corresponding dominant odds ratio is 1.359 (Table 23). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 156010845 of chromosome 4 is associated with an increased risk of developing colorectal cancer.

TABLE 23 rs no. 10517602 Chromosome; Position 4; 156010845 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.04835 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 T 825 134 11 Dominant 0.011861 1.359 1 T 804 180 12

Table 23A indicates SNPs found to be in strong linkage disequilibrium with rs10517602. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 23A Linked SNPs SNP r² Position on chr4 SEQ ID NO rs17031951 1.0 156007562 658 rs17031954 1.0 156008015 659 rs17031957 1.0 156009501 660 rs10517602 — 156010845 661 rs12501328 1.0 156019936 662 rs1876031 1.0 156020341 663 rs3775785 1.0 156027459 664 rs12507608 1.0 156029231 665 rs17032000 1.0 156030563 666 rs1392546 1.0 156032538 667 rs1500372 1.0 156033905 668

Example 24

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 114720973 of chromosome 5 was different from those without colorectal cancer (Table 24). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.000444 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.252 (Table 24). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 114720973 of chromosome 5 is associated with an increased risk of developing colorectal cancer.

TABLE 24 rs no. 2963765 Chromosome; Position 5; 114720973 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.65318 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 254 478 239 Trend 0.000444 1.252 1 A 207 484 305

Table 24A indicates SNPs found to be in strong linkage disequilibrium with rs2963765. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 24A Linked SNPs Position SNP r² on chr5 SEQ ID NO rs269511 0.677 114716570 669 rs12654556 0.74 114718052 670 rs10519405 0.525 114719100 671 rs10519406 0.525 114719186 672 rs2963765 — 114720973 673 rs2964560 1.0 114721020 674 rs269503 0.525 114724952 675 rs10463669 0.544 114727927 676 rs12657417 0.525 114728598 677 rs2925172 0.935 114729688 678 rs17383755 0.559 114730035 679 rs11241322 0.9 114730402 680 rs11241323 0.501 114731087 681 rs2963749 0.934 114734391 682 rs17383865 0.932 114735264 683 rs2963747 0.934 114735588 684 rs17137667 0.902 114735981 685 rs2925170 0.934 114736503 686 rs2591258 0.501 114737036 687 rs11740600 0.902 114737354 688 rs7715232 0.505 114739954 689 rs2198712 0.935 114741070 690 rs10477531 0.841 114742706 691 rs7703997 0.615 114743558 692 rs17137708 0.9 114743576 693 rs13162208 0.933 114744950 694 rs751485 0.934 114747047 695 rs897478 0.933 114747337 696 rs2016888 0.902 114747490 697

Example 25

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 121110284 of chromosome 5 was different from those without colorectal cancer (Table 25). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.003657 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.303 (Table 25). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 121110284 of chromosome 5 is associated with an increased risk of developing colorectal cancer.

TABLE 25 rs no. 1988515 Chromosome; Position 5; 121110284 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.71224 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 21 257 700 Trend 0.003657 1.303 1 A 11 216 754

Table 25A indicates SNPs found to be in strong linkage disequilibrium with rs1988515. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 25A Linked SNPs SNP r² Position on chr5 SEQ ID NO rs1988515 — 121110284 698

Example 26

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128145987 of chromosome 5 was different from those without colorectal cancer (Table 26). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.000992 based on permutation analysis, and the corresponding recessive odds ratio is 1.771 (Table 26). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 128145987 of chromosome 5 is associated with an increased risk of developing colorectal cancer.

TABLE 26 rs no. 10491268 Chromosome; Position 5; 128145987 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.24247 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 547 394 57 Recessive 0.000992 1.771 1 A 522 382 97

Table 26A indicates SNPs found to be in strong linkage disequilibrium with rs10491268. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 26A Linked SNPs SNP r² Position on chr5 SEQ ID NO rs247184 0.545 128103463 699 rs247195 0.545 128108152 700 rs247210 0.583 128113997 701 rs247094 0.583 128120050 702 rs10074635 0.503 128134369 703 rs10061806 1.0 128135572 704 rs7449021 1.0 128139763 705 rs17163935 0.56 128141175 706 rs10491268 — 128145987 707 rs17790915 0.512 128146786 708 rs1496344 0.576 128156553 709 rs1019137 0.545 128157693 710 rs7735162 0.961 128160641 711 rs7707454 0.926 128164258 712 rs2310808 0.545 128170372 713 rs10066082 0.816 128197696 714 rs10058629 0.778 128206257 715 rs17678073 0.778 128220969 716 rs2214369 0.816 128223084 717 rs6860974 0.778 128227979 718 rs10050439 0.778 128228401 719 rs7723679 0.767 128232311 720 rs7723683 0.777 128232320 721 rs10079808 0.778 128233576 722 rs1363170 0.769 128233727 723 rs13360809 0.778 128234493 724 rs13356389 0.778 128234617 725 rs17678190 0.778 128234806 726 rs17616306 0.778 128235438 727 rs7712212 0.778 128235745 728 rs7712497 0.778 128235767 729 rs7716412 0.778 128236078 730 rs13362019 0.778 128236528 731 rs9327496 0.523 128238639 732 rs13358000 0.778 128240119 733 rs4469239 0.776 128241301 734 rs13360401 0.583 128258653 735 rs6595867 0.578 128260778 736 rs6873372 0.552 128260800 737 rs6880855 0.558 128263313 738 rs1421889 0.61 128265259 739 rs9285913 0.558 128269933 740 rs10478827 0.544 128271956 741 rs9327500 0.591 128273703 742 rs13436689 0.549 128279649 743 rs13156417 0.558 128280539 744 rs10477690 0.555 128287628 745 rs6867677 0.554 128289750 746 rs6861915 0.558 128316551 747 rs10042256 0.567 128327389 748 rs11740497 0.556 128340511 749 rs10038006 0.54 128341528 750 rs17617241 0.516 128345166 751 rs10065480 0.516 128346380 752 rs11743701 0.525 128348967 753 rs3886286 0.525 128351543 754 rs7735034 0.524 128352581 755 rs7730969 0.525 128352924 756 rs11749027 0.558 128353107 757 rs17679250 0.525 128355391 758 rs17617329 0.525 128355483 759 rs3851463 0.525 128356081 760 rs6859805 0.642 128358774 761

Example 27

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 1032946 of chromosome 6, found within the LOC285768 gene, was different from those without colorectal cancer (Table 27). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.015463 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.199 (Table 27). These data further suggest that this marker, located within the LOC285768 gene, is associated with colorectal cancer risk and that the A allele at position 1032946 of chromosome 6 is associated with an increased risk of developing colorectal cancer.

TABLE 27 rs no. 9328033 Chromosome; Position 6; 1032946 Gene Name LOC285768 SEQ ID NO; Position 1772; 13622 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 1 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 59 370 571 Trend 0.015463 1.199 1 A 42 340 620

Table 27A indicates SNPs found to be in strong linkage disequilibrium with rs9328033. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 27A Linked SNPs Position SNP r² on chr6 SEQ ID NO rs9405439 0.795 1026731 762 rs9391899 0.837 1032864 763 rs9328033 — 1032946 764 rs7756730 0.756 1033885 765 rs7770094 0.756 1033964 766 rs10900904 0.75 1034131 767 rs10458112 0.756 1034217 768 rs6596783 0.744 1035056 769 rs6914197 0.72 1035451 770 rs9405441 0.753 1037138 771 rs6911992 0.72 1037761 772

Example 28

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 69521107 of chromosome 6, found within the BAI3 gene, was different from those without colorectal cancer (Table 28). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.00332, and the corresponding dominant odds ratio is 1.378 (Table 28). These data further suggest that this marker, located within the BAI3 gene, is associated with colorectal cancer risk and that the T allele at position 69521107 of chromosome 6 is associated with an increased risk of developing colorectal cancer.

TABLE 28 rs no. 10484791 Chromosome; Position 6; 69521107 Gene Name BAI3 SEQ ID NO; Position 1773; 116950 Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.01334 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 T 245 459 295 Dominant 0.00332 1.378 1 T 191 485 325

Table 28A indicates SNPs found to be in strong linkage disequilibrium with rs10484791. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 28A Linked SNPs SNP r² Position on chr6 SEQ ID NO rs9354792 0.628 69363616 773 rs2585614 0.595 69379328 774 rs2246104 0.656 69411039 775 rs2585627 0.656 69414352 776 rs2585626 0.656 69414862 777 rs2802694 0.807 69416925 778 rs2253759 0.868 69428738 779 rs2253866 0.746 69429357 780 rs2802689 0.865 69429728 781 rs2585622 0.709 69435338 782 rs2585621 0.716 69435377 783 rs2254654 0.837 69435704 784 rs3121775 0.69 69436412 785 rs6931872 0.743 69437088 786 rs2585592 0.656 69437132 787 rs7754835 0.69 69437929 788 rs2746125 0.746 69439747 789 rs2746127 0.746 69440936 790 rs2585597 0.715 69445347 791 rs2746141 0.837 69447873 792 rs2585598 0.69 69449271 793 rs2802684 0.742 69454318 794 rs2802683 0.868 69455343 795 rs2585599 0.733 69461590 796 rs2802680 0.776 69462851 797 rs2585600 0.718 69463179 798 rs2585604 0.776 69469800 799 rs2746132 0.718 69471343 800 rs715294 0.744 69483117 801 rs2802676 0.901 69483590 802 rs12206222 0.717 69486083 803 rs12210045 0.776 69490498 804 rs10945138 0.901 69496298 805 rs7768591 0.901 69497479 806 rs11752837 0.776 69504298 807 rs11752398 0.718 69504487 808 rs10945139 0.775 69511710 809 rs12154008 0.776 69513299 810 rs7745837 0.813 69517615 811 rs12201488 0.813 69518419 812 rs10484791 — 69521107 813

Example 29

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 83088471 of chromosome 6 was different from those without colorectal cancer (Table 29). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.001403, and the corresponding dominant odds ratio is 1.335 (Table 29). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 83088471 of chromosome 6 is associated with an increased risk of developing colorectal cancer.

TABLE 29 rs no. 508106 Chromosome; Position 6; 83088471 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.64887 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 T 496 409 90 Dominant 0.001403 1.335 1 T 425 460 111

Table 29A indicates SNPs found to be in strong linkage disequilibrium with rs508106. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 29A Linked SNPs SNP r² Position on chr6 SEQ ID NO rs2323642 0.644 82950808 814 rs540814 0.544 83037702 815 rs2753211 0.692 83052756 816 rs2753212 0.69 83052893 817 rs9344267 0.792 83059529 818 rs62953 0.763 83059811 819 rs529833 0.748 83063355 820 rs544734 0.958 83065585 821 rs554594 0.958 83065715 822 rs511002 1.0 83066965 823 rs507500 0.919 83067321 824 rs532219 1.0 83079412 825 rs577767 0.958 83086171 826 rs526833 0.957 83086772 827 rs7756828 1.0 83087733 828 rs508106 — 83088471 829 rs555844 0.919 83089659 830 rs1923137 1.0 83092525 831 rs1923138 0.957 83092537 832 rs723142 1.0 83094274 833 rs2180742 1.0 83094499 834 rs1547614 0.958 83094576 835 rs2145368 1.0 83095347 836 rs2180743 1.0 83095565 837 rs7762072 0.955 83095939 838 rs13191698 0.919 83096974 839 rs13207433 0.958 83097004 840 rs1321622 0.876 83097222 841 rs9353066 0.919 83098262 842 rs6907015 0.958 83098329 843 rs6930014 0.958 83098352 844 rs9353067 0.876 83100260 845 rs9353068 1.0 83101000 846 rs2024996 0.876 83103870 847 rs12527551 0.877 83104741 848 rs9344270 0.919 83105428 849 rs796398 0.958 83113039 850 rs770904 0.913 83114887 851 rs770897 0.782 83120523 852 rs770898 0.75 83122607 853 rs770894 0.773 83126442 854 rs770895 0.773 83127291 855 rs1570140 0.754 83129590 856 rs770911 0.754 83131084 857 rs1275806 0.658 83137358 858 rs770906 0.517 83140060 859 rs932614 0.517 83146661 860 rs9344274 0.508 83147795 861 rs1951006 0.52 83150543 862 rs9449462 0.507 83153296 863 rs9361914 0.505 83155501 864 rs714133 0.52 83162032 865 rs1998204 0.508 83163350 866 rs1853143 0.508 83165082 867 rs4706945 0.52 83165771 868 rs9449469 0.52 83167427 869 rs9449470 0.544 83167802 870 rs4706948 0.505 83168404 871 rs2875128 0.532 83169297 872 rs6912008 0.508 83169493 873 rs9449475 0.556 83170215 874 rs967730 0.553 83170490 875 rs967731 0.544 83170598 876 rs9361923 0.508 83172329 877

Example 30

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 83094274 of chromosome 6 was different from those without colorectal cancer (Table 30). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.001298, and the corresponding dominant odds ratio is 1.337 (Table 30). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 83094274 of chromosome 6 is associated with an increased risk of developing colorectal cancer.

TABLE 30 rs no. 723142 Chromosome; Position 6; 83094274 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.49209 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 T 501 404 91 Dominant 0.001298 1.337 1 T 430 458 110

Table 30A indicates SNPs found to be in strong linkage disequilibrium with rs723142. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 30A Linked SNPs SNP r² Position on chr6 SEQ ID NO rs2323642 0.621 82950808 814 rs540814 0.553 83037702 815 rs2753211 0.698 83052756 816 rs2753212 0.696 83052893 817 rs9344267 0.797 83059529 818 rs62953 0.768 83059811 819 rs529833 0.754 83063355 820 rs544734 0.959 83065585 821 rs554594 0.959 83065715 822 rs511002 1.0 83066965 823 rs507500 0.921 83067321 824 rs532219 1.0 83079412 825 rs577767 0.959 83086171 826 rs526833 0.958 83086772 827 rs7756828 1.0 83087733 828 rs508106 1.0 83088471 829 rs555844 0.921 83089659 830 rs1923137 1.0 83092525 831 rs1923138 0.958 83092537 832 rs723142 — 83094274 833 rs2180742 1.0 83094499 834 rs1547614 0.959 83094576 835 rs2145368 1.0 83095347 836 rs2180743 1.0 83095565 837 rs7762072 0.956 83095939 838 rs13191698 0.921 83096974 839 rs13207433 0.959 83097004 840 rs1321622 0.879 83097222 841 rs9353066 0.921 83098262 842 rs6907015 0.959 83098329 843 rs6930014 0.959 83098352 844 rs9353067 0.879 83100260 845 rs9353068 1.0 83101000 846 rs2024996 0.879 83103870 847 rs12527551 0.88 83104741 848 rs9344270 0.921 83105428 849 rs796398 0.959 83113039 850 rs770904 0.916 83114887 851 rs770897 0.786 83120523 852 rs770898 0.755 83122607 853 rs770894 0.778 83126442 854 rs770895 0.778 83127291 855 rs1570140 0.759 83129590 856 rs770911 0.759 83131084 857 rs1275806 0.664 83137358 858 rs770906 0.525 83140060 859 rs932614 0.525 83146661 860 rs9344274 0.517 83147795 861 rs1951006 0.528 83150543 862 rs9449462 0.515 83153296 863 rs9361914 0.514 83155501 864 rs714133 0.528 83162032 865 rs1998204 0.517 83163350 866 rs1853143 0.517 83165082 867 rs4706945 0.528 83165771 868 rs9449469 0.528 83167427 869 rs9449470 0.552 83167802 870 rs4706948 0.514 83168404 871 rs2875128 0.541 83169297 872 rs6912008 0.517 83169493 873 rs9449475 0.565 83170215 874 rs967730 0.562 83170490 875 rs967731 0.552 83170598 876 rs9361923 0.517 83172329 877

Example 31

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 129960703 of chromosome 6, found within the ARHGAP18 gene, was different from those without colorectal cancer (Table 31). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.000525 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.358 (Table 31). These data further suggest that this marker, located within the ARHGAP18 gene, is associated with colorectal cancer risk and that the C allele at position 129960703 of chromosome 6 is associated with an increased risk of developing colorectal cancer.

TABLE 31 rs no. 10499162 Chromosome; Position 6; 129960703 Gene Name ARHGAP18 SEQ ID NO; Position 1774; 112361 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.16957 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 746 215 9 Trend 0.000525 1.358 1 C 704 266 24

Table 31A indicates SNPs found to be in strong linkage disequilibrium with rs10499162. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 31A Linked SNPs SNP r² Position on chr6 SEQ ID NO rs9385502 0.928 129960436 878 rs10499162 — 129960703 879 rs9402145 1.0  129962477 880 rs9375636 0.635 129970245 881

Example 32

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 11585877 of chromosome 7, found within the KIAA0960 gene, was different from those without colorectal cancer (Table 32). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.008011 based on permutation analysis, and the corresponding recessive odds ratio is 1.596 (Table 32). These data further suggest that this marker, located within the KIAA0960 gene, is associated with colorectal cancer risk and that the G allele at position 11585877 of chromosome 7 is associated with an increased risk of developing colorectal cancer.

TABLE 32 rs no. 2355084 Chromosome; Position 7; 11585877 Gene Name KIAA0960 SEQ ID NO; Position 1775; 339055 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.27870 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 545 393 58 Recessive 0.008011 1.596 1 G 526 386 90

Table 32A indicates SNPs found to be in strong linkage disequilibrium with rs2355084. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 32A Linked SNPs SNP r² Position on chr7 SEQ ID NO rs2355084 — 11585877 882

Example 33

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 81559837 of chromosome 7, found within the CACNA2D1 gene, was different from those without colorectal cancer (Table 33). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.008433, and the corresponding dominant odds ratio is 1.455 (Table 33). These data further suggest that this marker, located within the CACNA2D1 gene, is associated with colorectal cancer risk and that the C allele at position 81559837 of chromosome 7 is associated with an increased risk of developing colorectal cancer.

TABLE 33 rs no. 10280428 Chromosome; Position 7; 81559837 Gene Name CACNA2D1 SEQ ID NO; Position 1776; 157620 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.01828 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 872 91 7 Dominant 0.008433 1.455 1 C 856 138 2

Table 33A indicates SNPs found to be in strong linkage disequilibrium with rs10280428. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 33A Linked SNPs SNP r² Position on chr7 SEQ ID NO rs11768310 0.88 81554149 883 rs10279911 0.915 81559478 884 rs10280428 — 81559837 885 rs11763784 1.0 81641687 886 rs11768220 0.901 81648931 887 rs11770457 0.88 81654315 888

Example 34

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 144767960 of chromosome 7 was different from those without colorectal cancer (Table 34). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.006242, and the corresponding dominant odds ratio is 1.590 (Table 34). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 144767960 of chromosome 7 is associated with an increased risk of developing colorectal cancer.

TABLE 34 rs no. 850470 Chromosome; Position 7; 144767960 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.07590 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 T 95 386 517 Dominant 0.006242 1.590 1 T 62 422 515

Table 34A indicates SNPs found to be in strong linkage disequilibrium with rs850470. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 34A Linked SNPs SNP r² Position on chr7 SEQ ID NO rs12532655 0.538 144628286 889 rs12534416 0.538 144628318 890 rs7805406 0.546 144628632 891 rs12533991 0.538 144629754 892 rs12533483 0.538 144629965 893 rs6968614 0.574 144630098 894 rs12374872 0.574 144635813 895 rs6968911 0.582 144643683 896 rs7784182 0.574 144645286 897 rs10280300 0.574 144646697 898 rs6964491 0.7 144669590 899 rs6951319 0.695 144669600 900 rs1357620 0.701 144671926 901 rs12531013 0.748 144672558 902 rs6952652 0.701 144674138 903 rs16882782 0.701 144676045 904 rs17169751 0.698 144676393 905 rs1357624 0.701 144678594 906 rs1357623 0.701 144678612 907 rs17169752 0.701 144680315 908 rs17169763 0.885 144718311 909 rs17169765 0.913 144720727 910 rs6960519 0.513 144733732 911 rs850456 0.72 144733992 912 rs850455 0.884 144734180 913 rs850454 0.884 144734239 914 rs850452 0.885 144734742 915 rs850450 0.885 144738529 916 rs850505 0.85 144744457 917 rs850502 0.885 144745645 918 rs850500 0.956 144745774 919 rs850499 0.885 144745875 920 rs850493 0.957 144751586 921 rs850492 0.958 144752182 922 rs850491 0.961 144752705 923 rs850490 0.957 144753415 924 rs850489 0.961 144753565 925 rs850488 0.961 144754173 926 rs850487 0.957 144755233 927 rs850486 0.961 144755604 928 rs850485 0.961 144755775 929 rs850483 0.961 144756961 930 rs850482 0.961 144757255 931 rs850480 1.0 144759437 932 rs850478 0.961 144760563 933 rs850476 0.961 144761726 934 rs850474 0.96 144766026 935 rs850472 0.961 144766794 936 rs850470 — 144767960 937 rs850468 0.693 144768118 938 rs850467 1.0 144768579 939 rs850466 1.0 144768715 940 rs850462 0.857 144770877 941 rs850461 0.85 144770905 942 rs850458 0.844 144771574 943 rs850457 0.854 144771653 944 rs860333 0.854 144771867 945 rs10246840 0.854 144774486 946 rs6952320 0.847 144774883 947 rs1079789 0.852 144776678 948 rs10952623 0.857 144777538 949 rs1468582 0.857 144778707 950 rs2372057 0.851 144781332 951 rs10952624 0.857 144781771 952 rs733171 0.857 144782495 953 rs10952625 0.857 144783026 954 rs12667814 0.618 144783666 955 rs6976909 0.857 144784599 956 rs2079830 0.849 144785299 957 rs12154287 0.533 144788902 958 rs1990347 0.857 144791211 959 rs10267840 0.857 144793063 960 rs10808035 0.857 144796105 961 rs11763425 0.857 144799583 962 rs2191275 0.887 144799675 963 rs12535408 0.856 144800213 964 rs6961951 0.857 144800438 965 rs6962101 0.857 144800519 966 rs6979892 0.805 144800830 967 rs12703731 0.58 144801300 968 rs6951436 0.857 144802085 969 rs11761238 0.821 144802576 970 rs10228710 0.857 144803188 971 rs7810370 0.857 144803650 972 rs6464691 0.857 144804012 973 rs6962254 0.857 144804167 974 rs2888244 0.854 144805193 975 rs4285408 0.857 144805467 976 rs11764219 0.857 144806025 977 rs6944748 0.857 144806327 978 rs6969500 0.809 144806354 979 rs10952627 0.857 144808010 980 rs6966867 0.857 144810732 981 rs10237200 0.849 144814121 982 rs10266218 0.846 144814527 983 rs850571 0.852 144818301 984 rs850570 0.857 144819907 985

Example 35

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 149242026 of chromosome 7 was different from those without colorectal cancer (Table 35). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.001661 based on permutation analysis, and the corresponding recessive odds ratio is 1.418 (Table 35). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 149242026 of chromosome 7 is associated with an increased risk of developing colorectal cancer.

TABLE 35 rs no. 3864498 Chromosome; Position 7; 149242026 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.48562 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 20 215 704 Recessive 0.001661 1.418 1 G 17 168 786

Table 35A indicates SNPs found to be in strong linkage disequilibrium with rs3864498. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 35A Linked SNPs SNP r² Position on chr7 SEQ ID NO rs4015699 0.699 149201414 986 rs4725865 0.779 149210939 987 rs13227764 0.687 149213761 988 rs4367449 0.543 149214960 989 rs6947979 0.844 149219765 990 rs3864498 — 149242026 991 rs4406321 0.907 149242664 992 rs17173853 0.92  149243724 993

Example 36

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 4257764 of chromosome 8, found within the CSMD1 gene, was different from those without colorectal cancer (Table 36). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.025004 based on permutation analysis, and the corresponding recessive odds ratio is 1.228 (Table 36). These data further suggest that this marker, located within the CSMD1 gene, is associated with colorectal cancer risk and that the A allele at position 4257764 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 36 rs no. 10503262 Chromosome; Position 8; 4257764 Gene Name CSMD1 SEQ ID NO; Position 1777; 581973 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.27772 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 72 360 539 Recessive 0.025004 1.228 1 A 63 330 602

Table 36A indicates SNPs found to be in strong linkage disequilibrium with rs10503262. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 36A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs10089026 0.958 4252805 994 rs10092807 1.0  4257185 995 rs10503262 — 4257764 996

Example 37

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 9440613 of chromosome 8 was different from those without colorectal cancer (Table 37). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.049874 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.144 (Table 37). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 9440613 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 37 rs no. 6601328 Chromosome; Position 8; 9440613 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.08727 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 26 252 931 Trend 0.049874 1.144 1 A 8 248 974

Table 37A indicates SNPs found to be in strong linkage disequilibrium with rs6601328. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 37A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs17150201 0.88 9426711 997 rs1471203 0.803 9431741 998 rs7009486 0.891 9436057 999 rs13261395 1.0 9436101 1000 rs4841169 0.891 9436786 1001 rs4840423 1.0 9437029 1002 rs4841171 1.0 9437099 1003 rs11785485 1.0 9439838 1004 rs7388554 0.88 9440072 1005 rs6601328 — 9440613 1006 rs11781665 1.0 9444872 1007 rs7013834 1.0 9452052 1008 rs13274310 1.0 9458679 1009 rs13265363 0.891 9460336 1010 rs11784858 0.785 9463104 1011 rs13270240 0.847 9468129 1012 rs11775432 1.0 9480306 1013 rs4551359 1.0 9503674 1014 rs11774818 1.0 9523873 1015 rs4841186 1.0 9526021 1016 rs4840432 1.0 9526193 1017 rs4535743 0.891 9529470 1018 rs11994018 1.0 9531111 1019 rs11991547 1.0 9538857 1020 rs7839648 0.891 9541393 1021 rs4128324 1.0 9546289 1022 rs1393 1.0 9549119 1023 rs11780274 1.0 9558649 1024 rs13250838 1.0 9563755 1025 rs13264510 1.0 9568067 1026 rs13261385 1.0 9568084 1027 rs4570159 1.0 9568712 1028 rs13259379 0.891 9640154 1029 rs4289816 0.88 9645506 1030 rs17734024 0.891 9673180 1031

Example 38

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 55701610 of chromosome 8, found within the RP1 gene, was different from those without colorectal cancer (Table 38). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.003739 based on permutation analysis, and the corresponding recessive odds ratio is 1.279 (Table 38). These data further suggest that this marker, located within the RP1 gene, is associated with colorectal cancer risk and that the G allele at position 55701610 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 38 rs no. 444772 Chromosome; Position 8; 55701610 Gene Name RP1 SEQ ID NO; Position 1778; 10431 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.88723 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 102 471 554 Recessive 0.003739 1.279 1 G 87 421 628

Table 38A indicates SNPs found to be in strong linkage disequilibrium with rs444772. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 38A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs421844 0.95 55688038 1032 rs435326 0.952 55688723 1033 rs396881 0.954 55688788 1034 rs446102 0.954 55689106 1035 rs702761 1.0 55691506 1036 rs145290 1.0 55692165 1037 rs428854 1.0 55698923 1038 rs429668 1.0 55699691 1039 rs444772 — 55701610 1040 rs446227 1.0 55704003 1041 rs414352 1.0 55704066 1042 rs441800 1.0 55704170 1043 rs388912 1.0 55714151 1044 rs376055 1.0 55718398 1045 rs448744 1.0 55720864 1046 rs433265 1.0 55724371 1047 rs421469 1.0 55724624 1048 rs383666 1.0 55725409 1049 rs509273 1.0 55729655 1050 rs428630 1.0 55732233 1051 rs369565 1.0 55734727 1052 rs858428 1.0 55734972 1053 rs499324 1.0 55735628 1054 rs409429 1.0 55735791 1055 rs426380 0.909 55736905 1056 rs439539 1.0 55738068 1057 rs433881 1.0 55740834 1058 rs437439 1.0 55741606 1059 rs450496 1.0 55742554 1060 rs446153 1.0 55747804 1061 rs453186 1.0 55748460 1062 rs371043 1.0 55752508 1063 rs394020 1.0 55760756 1064 rs395862 1.0 55761309 1065 rs858396 1.0 55776456 1066 rs893361 1.0 55783865 1067 rs6473950 0.955 55801936 1068 rs1437785 0.955 55811566 1069 rs2043774 0.955 55819136 1070 rs7000259 0.955 55821626 1071 rs4737673 0.955 55823685 1072 rs1509678 0.955 55825618 1073 rs2375220 0.955 55845129 1074 rs1553764 0.955 55858095 1075 rs1498181 0.955 55861650 1076 rs1498182 0.866 55870126 1077 rs1039842 0.955 55880446 1078 rs9298510 0.955 55883850 1079 rs1498189 0.802 55886453 1080

Example 39

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 105447572 of chromosome 8 was different from those without colorectal cancer (Table 39). The dominant test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.0698, and the corresponding dominant odds ratio is 1.184 (Table 39). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 105447572 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 39 rs no. 2853129 Chromosome; Position 8; 105447572 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.13044 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 G 917 264 27 Dominant 0.0698 1.184 1 G 894 312 24

Table 39A indicates SNPs found to be in strong linkage disequilibrium with rs2853129. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 39A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs2853129 — 105447572 1081

Example 40

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128476287 of chromosome 8 was different from those without colorectal cancer (Table 40). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.021659 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.305 (Table 40). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 128476287 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 40 rs no. 16902149 Chromosome; Position 8; 128476287 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.04399 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 C 959 124 0 Trend 0.021659 1.305 1 C 824 134 5

Table 40A indicates SNPs found to be in strong linkage disequilibrium with rs16902149. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 40A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs16902149 — 128476287 1082 rs17467139 1.0 128481192 1089

Example 41

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128476625 of chromosome 8 was different from those without colorectal cancer (Table 41). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.000282 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.264 (Table 41). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 128476625 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 41 rs no. 10505477 Chromosome; Position 8; 128476625 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 1 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 251 486 234 Trend 0.000282 1.264 1 A 209 478 309

Table 41A indicates SNPs found to be in strong linkage disequilibrium with rs10505477. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 41A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs10505477 — 128476625 1084 rs10808556 0.627 128482329 1090 rs6983267 0.935 128482487 1091 rs3847137 0.598 128483680 1092 rs10505474 0.632 128486686 1094 rs2060776 0.609 128489299 1096 rs4871788 0.609 128490967 1097 rs7837328 0.609 128492309 1098 rs7837626 0.609 128492523 1099 rs7837644 0.609 128492580 1100 rs10956368 0.586 128492832 1101 rs10956369 0.609 128492999 1102 rs871135 0.609 128495575 1104

Example 42

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128477298 of chromosome 8 was different from those without colorectal cancer (Table 42). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.001921, and the corresponding dominant odds ratio is 1.337 (Table 42). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 128477298 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 42 rs no. 10505476 Chromosome; Position 8; 128477298 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.19082 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 480 357 52 Dominant 0.001921 1.337 1 T 439 434 66

Table 42A indicates SNPs found to be in strong linkage disequilibrium with rs10505476. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 42A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs10505476 — 128477298 1086 rs10808556 0.602 128482329 1090 rs3847137 0.557 128483680 1092 rs10505474 0.579 128486686 1094 rs2060776 0.601 128489299 1096 rs4871788 0.601 128490967 1097 rs7837328 0.601 128492309 1098 rs7837626 0.601 128492523 1099 rs7837644 0.601 128492580 1100 rs10956368 0.557 128492832 1101 rs10956369 0.601 128492999 1102 rs871135 0.601 128495575 1104

Example 43

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128483680 of chromosome 8 was different from those without colorectal cancer (Table 43). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.004512 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.193 (Table 43). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 128483680 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 43 rs no. 3847137 Chromosome; Position 8; 128483680 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.40673 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 359 521 169 Trend 0.004512 1.193 1 C 313 518 214

Table 43A indicates SNPs found to be in strong linkage disequilibrium with rs3847137. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 43A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs3847136 0.581 128476372 1083 rs10505477 0.598 128476625 1084 rs10505476 0.557 128477298 1086 rs11985829 0.524 128478414 1087 rs10808556 0.956 128482329 1090 rs6983267 0.556 128482487 1091 rs3847137 — 128483680 1092 rs7013278 0.663 128484074 1093 rs10505474 0.963 128486686 1094 rs2060776 0.928 128489299 1096 rs4871788 0.928 128490967 1097 rs7837328 0.928 128492309 1098 rs7837626 0.928 128492523 1099 rs7837644 0.928 128492580 1100 rs10956368 0.893 128492832 1101 rs10956369 0.928 128492999 1102 rs7014346 0.701 128493974 1103 rs871135 0.928 128495575 1104

Example 44

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128486686 of chromosome 8 was different from those without colorectal cancer (Table 44). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.004329 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.199 (Table 44). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 128486686 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 44 rs no. 10505474 Chromosome; Position 8; 128486686 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.64397 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 355 485 155 Trend 0.004329 1.199 1 T 308 482 198

Table 44A indicates SNPs found to be in strong linkage disequilibrium with rs10505474. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 44A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs3847136 0.608 128476372 1083 rs10505477 0.632 128476625 1084 rs10505476 0.579 128477298 1086 rs11985829 0.545 128478414 1087 rs10808556 1.0 128482329 1090 rs6983267 0.591 128482487 1091 rs3847137 0.963 128483680 1092 rs7013278 0.695 128484074 1093 rs10505474 — 128486686 1094 rs2060776 0.963 128489299 1096 rs4871788 0.963 128490967 1097 rs7837328 0.963 128492309 1098 rs7837626 0.963 128492523 1099 rs7837644 0.963 128492580 1100 rs10956368 0.927 128492832 1101 rs10956369 0.963 128492999 1102 rs7014346 0.727 128493974 1103 rs871135 0.963 128495575 1104

Example 45

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128487118 of chromosome 8 was different from those without colorectal cancer (Table 45). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.008718, and the corresponding dominant odds ratio is 1.293 (Table 45). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 128487118 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 45 rs no. 10505473 Chromosome; Position 8; 128487118 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.20587 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 722 262 16 Dominant 0.008718 1.293 1 T 669 312 21

Table 45A indicates SNPs found to be in strong linkage disequilibrium with rs10505473. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 45A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs12334317 1.0 128477246 1085 rs10505473 — 128487118 1095 rs9297756 0.841 128509349 1106 rs7357368 1.0 128512569 1107 rs7831606 0.69 128524876 1108

Example 46

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128492832 of chromosome 8 was different from those without colorectal cancer (Table 46). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.006508 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.180 (Table 46). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 128492832 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 46 rs no. 10956368 Chromosome; Position 8; 128492832 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.60762 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 393 519 159 Trend 0.006508 1.180 1 T 347 509 203

Table 46A indicates SNPs found to be in strong linkage disequilibrium with rs10956368. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 46A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs10505477 0.586 128476625 1084 rs10505476 0.557 128477298 1086 rs10808556 0.911 128482329 1090 rs6983267 0.548 128482487 1091 rs3847137 0.893 128483680 1092 rs7013278 0.586 128484074 1093 rs10505474 0.927 128486686 1094 rs2060776 0.962 128489299 1096 rs4871788 0.962 128490967 1097 rs7837328 0.962 128492309 1098 rs7837626 0.962 128492523 1099 rs7837644 0.962 128492580 1100 rs10956368 — 128492832 1101 rs10956369 0.962 128492999 1102 rs7014346 0.713 128493974 1103 rs871135 0.962 128495575 1104

Example 47

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128492999 of chromosome 8 was different from those without colorectal cancer (Table 47). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.002283 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.208 (Table 47). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 128492999 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 47 rs no. 10956369 Chromosome; Position 8; 128492999 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.56463 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 375 518 165 Trend 0.002283 1.208 1 T 322 516 211

Table 47A indicates SNPs found to be in strong linkage disequilibrium with rs10956369. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 47A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs3847136 0.553 128476372 1083 rs10505477 0.609 128476625 1084 rs10505476 0.601 128477298 1086 rs10808556 0.955 128482329 1090 rs6983267 0.569 128482487 1091 rs3847137 0.928 128483680 1092 rs7013278 0.64 128484074 1093 rs10505474 0.963 128486686 1094 rs2060776 1.0 128489299 1096 rs4871788 1.0 128490967 1097 rs7837328 1.0 128492309 1098 rs7837626 1.0 128492523 1099 rs7837644 1.0 128492580 1100 rs10956368 0.962 128492832 1101 rs10956369 — 128492999 1102 rs7014346 0.755 128493974 1103 rs871135 1.0 128495575 1104

Example 48

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128493974 of chromosome 8 was different from those without colorectal cancer (Table 48). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.000759 based on permutation analysis, and the corresponding recessive odds ratio is 1.529 (Table 48). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 128493974 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 48 rs no. 7014346 Chromosome; Position 8; 128493974 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.09641 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 429 517 124 Recessive 0.000759 1.529 1 A 378 505 177

Table 48A indicates SNPs found to be in strong linkage disequilibrium with rs7014346. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 48A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs3847136 0.714 128476372 1083 rs11985829 0.644 128478414 1087 rs10808555 0.505 128478693 1088 rs10808556 0.748 128482329 1090 rs3847137 0.701 128483680 1092 rs7013278 0.944 128484074 1093 rs10505474 0.727 128486686 1094 rs2060776 0.755 128489299 1096 rs4871788 0.755 128490967 1097 rs7837328 0.755 128492309 1098 rs7837626 0.755 128492523 1099 rs7837644 0.755 128492580 1100 rs10956368 0.713 128492832 1101 rs10956369 0.755 128492999 1102 rs7014346 — 128493974 1103 rs871135 0.755 128495575 1104 rs7842552 0.642 128500876 1105

Example 49

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 128500876 of chromosome 8 was different from those without colorectal cancer (Table 49).

The trend test for risk associated with carrying the G allele had an empirical p-value of 0.002018 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.240 (Table 49). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 128500876 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 49 rs no. 7842552 Chromosome; Position 8; 128500876 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.87942 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 G 510 424 85 Trend 0.002018 1.240 1 G 430 450 107

Table 49A indicates SNPs found to be in strong linkage disequilibrium with rs7842552. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 49A Linked SNPs SNP r² Position on chr8 SEQ ID NO rs7013278 0.53 128484074 1093 rs7014346 0.642 128493974 1103 rs7842552 — 128500876 1105

Example 50

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 138583352 of chromosome 8 was different from those without colorectal cancer (Table 50).

The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.000829 based on permutation analysis, and the corresponding recessive odds ratio is 2.664 (Table 50). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 138583352 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 50 rs no. 1399176 Chromosome; Position 8; 138583352 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.04904 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 686 269 15 Recessive 0.000829 2.664 1 C 666 290 40

Table 50A indicates SNPs found to be in strong linkage disequilibrium with rs1399176. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 50A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs4909649 0.835 138448609 1109 rs4909652 0.835 138448978 1110 rs7000235 0.835 138450507 1111 rs7833216 0.835 138450935 1112 rs6986763 0.835 138451287 1113 rs4265216 0.821 138452272 1114 rs4391470 0.835 138452507 1115 rs13249389 0.834 138452835 1116 rs10102751 0.835 138453471 1117 rs4532628 0.835 138454113 1118 rs4279630 0.829 138454197 1119 rs4474054 0.835 138454235 1120 rs4909654 0.835 138454833 1121 rs4292724 0.835 138455486 1122 rs12541665 0.835 138455728 1123 rs4909657 0.82 138456184 1124 rs4909367 0.652 138456296 1125 rs7820493 0.835 138456395 1126 rs7837229 0.835 138457265 1127 rs13253269 0.83 138458205 1128 rs7014387 0.835 138458287 1129 rs7826913 0.835 138458607 1130 rs6577786 0.835 138459228 1131 rs7835685 0.835 138459736 1132 rs4909658 0.833 138460258 1133 rs4909659 0.835 138460320 1134 rs4909660 0.835 138460491 1135 rs6577788 0.835 138461455 1136 rs6577789 0.835 138461471 1137 rs7845225 0.835 138461926 1138 rs7827162 0.835 138462319 1139 rs4131207 0.796 138467267 1140 rs4131208 0.835 138467277 1141 rs7016247 0.835 138467539 1142 rs7007938 0.835 138469853 1143 rs10875404 0.835 138469883 1144 rs6577790 0.835 138472916 1145 rs4909665 0.835 138473941 1146 rs6577792 0.828 138477490 1147 rs4582597 0.681 138481482 1148 rs10098545 0.819 138482393 1149 rs2943199 0.86 138490184 1150 rs2960100 0.835 138498734 1151 rs11166725 0.958 138545196 1152 rs17629911 0.958 138546484 1153 rs10505682 0.837 138551497 1154 rs17632067 1.0 138576626 1155 rs11786383 1.0 138578139 1156 rs11773949 0.628 138580074 1157 rs1399176 — 138583352 1158 rs10505684 0.628 138585809 1159 rs7816962 0.628 138585968 1160 rs6577803 0.606 138586498 1161 rs6996799 0.606 138588282 1162 rs17683816 0.959 138590203 1163 rs12677749 0.959 138590751 1164 rs6981747 0.957 138594903 1165 rs6998164 0.959 138598108 1166 rs4384013 0.958 138601596 1167 rs4625065 0.959 138601771 1168 rs11786764 0.959 138603600 1169 rs11786786 0.959 138603658 1170 rs11776612 0.959 138603708 1171 rs1913453 0.959 138604408 1172 rs17684894 0.959 138604979 1173 rs17633888 0.959 138607006 1174 rs17633935 0.959 138607169 1175 rs17685141 0.956 138607178 1176 rs12677813 0.959 138608732 1177 rs11780534 0.959 138610100 1178 rs11777429 0.958 138610110 1179 rs17634044 0.959 138610517 1180 rs11166729 0.959 138611185 1181 rs1514199 0.959 138611655 1182 rs1514200 0.954 138611699 1183 rs1514201 0.953 138611757 1184 rs11780105 0.954 138612308 1185 rs12375358 0.959 138614096 1186 rs10505685 0.958 138614490 1187 rs17685382 0.959 138614687 1188 rs17634252 0.959 138615037 1189 rs17634276 0.957 138615093 1190 rs11778762 0.959 138615852 1191 rs1514202 0.954 138616621 1192 rs1514203 0.959 138616711 1193 rs1514204 0.959 138616778 1194

Example 51

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 138614490 of chromosome 8 was different from those without colorectal cancer (Table 51). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.002867 based on permutation analysis, and the corresponding recessive odds ratio is 2.258 (Table 51). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 138614490 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 51 rs no. 10505685 Chromosome; Position 8; 138614490 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.12615 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 673 278 19 Recessive 0.002867 2.258 1 C 654 299 43

Table 51A indicates SNPs found to be in strong linkage disequilibrium with rs10505685. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 51A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs4909649 0.794 138448609 1109 rs4909652 0.794 138448978 1110 rs7000235 0.794 138450507 1111 rs7833216 0.794 138450935 1112 rs6986763 0.794 138451287 1113 rs4265216 0.777 138452272 1114 rs4391470 0.794 138452507 1115 rs13249389 0.793 138452835 1116 rs10102751 0.794 138453471 1117 rs4532628 0.794 138454113 1118 rs4279630 0.788 138454197 1119 rs4474054 0.794 138454235 1120 rs4909654 0.794 138454833 1121 rs4292724 0.794 138455486 1122 rs12541665 0.794 138455728 1123 rs4909657 0.776 138456184 1124 rs4909367 0.641 138456296 1125 rs7820493 0.794 138456395 1126 rs7837229 0.794 138457265 1127 rs13253269 0.789 138458205 1128 rs7014387 0.794 138458287 1129 rs7826913 0.794 138458607 1130 rs6577786 0.794 138459228 1131 rs7835685 0.794 138459736 1132 rs4909658 0.792 138460258 1133 rs4909659 0.794 138460320 1134 rs4909660 0.794 138460491 1135 rs6577788 0.794 138461455 1136 rs6577789 0.794 138461471 1137 rs7845225 0.794 138461926 1138 rs7827162 0.794 138462319 1139 rs4131207 0.755 138467267 1140 rs4131208 0.794 138467277 1141 rs7016247 0.794 138467539 1142 rs7007938 0.794 138469853 1143 rs10875404 0.794 138469883 1144 rs6577790 0.794 138472916 1145 rs4909665 0.794 138473941 1146 rs6577792 0.786 138477490 1147 rs4582597 0.643 138481482 1148 rs10098545 0.774 138482393 1149 rs2943199 0.815 138490184 1150 rs2960100 0.794 138498734 1151 rs11166725 0.916 138545196 1152 rs17629911 0.916 138546484 1153 rs10505682 0.797 138551497 1154 rs17632067 0.957 138576626 1155 rs11786383 0.958 138578139 1156 rs11773949 0.585 138580074 1157 rs1399176 0.958 138583352 1158 rs10505684 0.585 138585809 1159 rs7816962 0.585 138585968 1160 rs6577803 0.626 138586498 1161 rs6996799 0.626 138588282 1162 rs17683816 1.0 138590203 1163 rs12677749 1.0 138590751 1164 rs6981747 1.0 138594903 1165 rs6998164 1.0 138598108 1166 rs4384013 0.957 138601596 1167 rs4625065 1.0 138601771 1168 rs11786764 1.0 138603600 1169 rs11786786 1.0 138603658 1170 rs11776612 1.0 138603708 1171 rs1913453 1.0 138604408 1172 rs17684894 1.0 138604979 1173 rs17633888 1.0 138607006 1174 rs17633935 1.0 138607169 1175 rs17685141 1.0 138607178 1176 rs12677813 1.0 138608732 1177 rs11780534 1.0 138610100 1178 rs11777429 1.0 138610110 1179 rs17634044 1.0 138610517 1180 rs11166729 1.0 138611185 1181 rs1514199 1.0 138611655 1182 rs1514200 1.0 138611699 1183 rs1514201 1.0 138611757 1184 rs11780105 1.0 138612308 1185 rs12375358 1.0 138614096 1186 rs10505685 — 138614490 1187 rs17685382 1.0 138614687 1188 rs17634252 1.0 138615037 1189 rs17634276 1.0 138615093 1190 rs11778762 1.0 138615852 1191 rs1514202 1.0 138616621 1192 rs1514203 1.0 138616711 1193 rs1514204 1.0 138616778 1194

Example 52

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 141587219 of chromosome 8 was different from those without colorectal cancer (Table 52). The dominant test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.0772, and the corresponding dominant odds ratio is 1.172 (Table 52). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 141587219 of chromosome 8 is associated with an increased risk of developing colorectal cancer.

TABLE 52 rs no. 1057083 Chromosome; Position 8; 141587219 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.04921 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 892 283 34 Dominant 0.0772 1.172 1 A 867 337 24

Table 52A indicates SNPs found to be in strong linkage disequilibrium with rs1057083. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 52A Linked SNPs Position SNP r² on chr8 SEQ ID NO rs12676904 0.806 141567935 1195 rs4961309 1.0 141583366 1196 rs1057083 — 141587219 1197 rs6578111 1.0 141589763 1198 rs4246131 0.752 141595220 1199 rs4961323 1.0 141595413 1200 rs10216653 1.0 141596167 1201 rs4610723 0.951 141596488 1202 rs7388327 0.521 141597272 1203

Example 53

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 6355683 of chromosome 9 was different from those without colorectal cancer (Table 53). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.005611 based on permutation analysis, and the corresponding recessive odds ratio is 1.289 (Table 53). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 6355683 of chromosome 9 is associated with an increased risk of developing colorectal cancer.

TABLE 53 rs no. 719725 Chromosome; Position 9; 6355683 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.50139 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 138 479 378 Recessive 0.005611 1.289 1 A 121 435 439

Table 53A indicates SNPs found to be in strong linkage disequilibrium with rs719725. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 53A Linked SNPs Position SNP r² on chr9 SEQ ID NO rs744567 0.509 6282602 1204 rs17756142 0.553 6291578 1205 rs1322166 0.57 6299862 1206 rs17705436 0.553 6300908 1207 rs4742179 0.518 6314376 1208 rs10758764 0.511 6316825 1209 rs10491836 0.649 6321421 1210 rs16924356 0.615 6321610 1211 rs721352 0.518 6322901 1212 rs7850988 0.649 6325760 1213 rs731585 0.546 6332328 1214 rs2169282 0.717 6340235 1215 rs16924428 0.624 6341111 1216 rs10975552 0.966 6341834 1217 rs10975553 1.0 6342819 1218 rs7022186 1.0 6349144 1219 rs7851246 0.649 6352365 1220 rs10975558 0.649 6354449 1221 rs7875812 1.0 6354533 1222 rs719724 0.84 6355614 1223 rs719725 — 6355683 1224 rs7860427 0.74 6375637 1225 rs7025295 0.965 6385247 1226 rs7850497 0.782 6385540 1227 rs10217561 0.782 6386245 1228 rs10815428 0.686 6390030 1229 rs7045097 0.816 6392856 1230 rs10758783 0.816 6397799 1231 rs10739097 0.834 6397843 1232 rs7865955 0.84 6398247 1233 rs7857628 0.966 6399874 1234

Example 54

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 73642109 of chromosome 9 was different from those without colorectal cancer (Table 54). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.005462 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.489 (Table 54). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 73642109 of chromosome 9 is associated with an increased risk of developing colorectal cancer.

TABLE 54 rs no. 10512028 Chromosome; Position 9; 73642109 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.28078 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 6 113 852 Trend 0.005462 1.489 1 A 3 81 911

Table 54A indicates SNPs found to be in strong linkage disequilibrium with rs10512028. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 54A Linked SNPs SNP r² Position on chr9 SEQ ID NO rs4288438 1.0 73606988 1235 rs6560355 1.0 73607164 1236 rs1585251 1.0 73607569 1237 rs4745250 1.0 73612124 1238 rs7044457 1.0 73613027 1239 rs2061399 1.0 73614943 1240 rs2061398 1.0 73615076 1241 rs2061396 1.0 73615232 1242 rs2061395 1.0 73616781 1243 rs10781152 1.0 73617303 1244 rs4745254 1.0 73618675 1245 rs2168884 1.0 73619146 1246 rs4745255 1.0 73622095 1247 rs4745256 1.0 73622395 1248 rs4745257 1.0 73622439 1249 rs4745258 1.0 73625852 1250 rs4745259 1.0 73626601 1251 rs4745260 1.0 73626706 1252 rs7389572 1.0 73627824 1253 rs10746927 1.0 73628740 1254 rs7048840 1.0 73629704 1255 rs4744695 1.0 73633747 1256 rs981197 1.0 73634385 1257 rs1458489 1.0 73635467 1258 rs1379909 1.0 73635691 1259 rs1379910 1.0 73635782 1260 rs1902976 1.0 73636447 1261 rs1902978 1.0 73636612 1262 rs7026566 1.0 73636831 1263 rs1379911 1.0 73638980 1264 rs7027893 1.0 73639771 1265 rs7039655 1.0 73639895 1266 rs4468001 1.0 73640222 1267 rs10512028 — 73642109 1268 rs999791 1.0 73642315 1269 rs17059425 1.0 73643177 1270

Example 55

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 79353007 of chromosome 9 was different from those without colorectal cancer (Table 55). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.016576 based on permutation analysis, and the corresponding recessive odds ratio is 1.573 (Table 55). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 79353007 of chromosome 9 is associated with an increased risk of developing colorectal cancer.

TABLE 55 rs no. 946807 Chromosome; Position 9; 79353007 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.39477 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 0 76 895 Recessive 0.016576 1.573 1 T 1 50 945

Table 55A indicates SNPs found to be in strong linkage disequilibrium with rs946807. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 55A Linked SNPs Position SNP r² on chr9 SEQ ID NO rs946807 — 79353007 1271 rs7040700 0.59 79353924 1272 rs12005727 1.0 79356465 1273 rs12347524 1.0 79356737 1274 rs10867398 0.536 79359981 1275

Example 56

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 110115339 of chromosome 9 was different from those without colorectal cancer (Table 56). The recessive test for risk associated with carrying the A allele had an empirical p-value of 0.009423 based on permutation analysis, and the corresponding recessive odds ratio is 1.294 (Table 56). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 110115339 of chromosome 9 is associated with an increased risk of developing colorectal cancer.

TABLE 56 rs no. 10512404 Chromosome; Position 9; 110115339 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.04658 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 A 44 278 649 Recessive 0.009423 1.294 1 A 37 239 720

Table 56A indicates SNPs found to be in strong linkage disequilibrium with rs10512404. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 56A Linked SNPs SNP r² Position on chr9 SEQ ID NO rs10512404 — 110115339 1276 rs10980301 1.0 110130428 1277

Example 57

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 4453422 of chromosome 11, found within the OR52K3P gene, was different from those without colorectal cancer (Table 57). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.002811, and the corresponding dominant odds ratio is 1.290 (Table 57). These data further suggest that this marker, located within the OR52K3P gene, is associated with colorectal cancer risk and that the T allele at position 4453422 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 57 rs no. 2278170 Chromosome; Position 11; 4453422 Gene Name OR52K3P SEQ ID NO; Position 1779; 808 Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.05835 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 570 431 107 Dominant 0.002811 1.290 1 T 497 497 108

Table 57A indicates SNPs found to be in strong linkage disequilibrium with rs2278170. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 57A Linked SNPs Position SNP r² on chr11 SEQ ID NO rs167948 0.593 4430296 1278 rs10836079 0.835 4430392 1279 rs191761 0.573 4430569 1280 rs7395324 1.0 4434860 1281 rs11032345 1.0 4440254 1282 rs10836102 1.0 4442501 1283 rs11032351 1.0 4443277 1284 rs11032354 0.928 4443753 1285 rs11032359 0.925 4444427 1286 rs11032361 0.929 4444806 1287 rs10768026 1.0 4446686 1288 rs331502 1.0 4448408 1289 rs11032378 0.929 4449042 1290 rs11032381 0.929 4449105 1291 rs890416 0.929 4449910 1292 rs890417 0.927 4450407 1293 rs890418 0.929 4450528 1294 rs331503 1.0 4451604 1295 rs9633905 1.0 4453189 1296 rs2278170 — 4453422 1297 rs2278171 1.0 4453492 1298 rs2278172 0.964 4453537 1299 rs2278173 1.0 4453673 1300 rs11032407 1.0 4454017 1301 rs9633900 1.0 4454894 1302 rs2641405 0.658 4532655 1303 rs11032827 0.577 4543829 1304

Example 58

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 5766249 of chromosome 11, found within the OR52N1 gene, was different from those without colorectal cancer (Table 58). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.002453, and the corresponding dominant odds ratio is 1.584 (Table 58). These data further suggest that this marker, located within the OR52N1 gene, is associated with colorectal cancer risk and that the C allele at position 5766249 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 58 rs no. 10769224 Chromosome; Position 11; 5766249 Gene Name OR52N1 SEQ ID NO; Position 1780; 374 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.07909 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 C 117 453 559 Dominant 0.002453 1.584 1 C 77 502 553

Table 58A indicates SNPs found to be in strong linkage disequilibrium with rs10769224. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 58A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs7948009 0.819 5766124 1305 rs10769224 — 5766249 1306 rs10742787 1.0 5766322 1307 rs7924824 1.0 5768065 1308 rs10838648 0.698 5772861 1309 rs10769232 1.0 5774897 1310 rs7949986 1.0 5775192 1311 rs1377512 1.0 5776193 1312 rs7940926 1.0 5778275 1313 rs10769235 1.0 5779169 1314 rs10769236 1.0 5779183 1315 rs4758099 1.0 5779725 1316 rs4758100 0.804 5779774 1317 rs4758101 1.0 5779871 1318 rs7484069 0.826 5780048 1319 rs11039085 0.524 5780227 1320 rs7937133 1.0 5781044 1321 rs1453419 1.0 5781459 1322 rs1453418 1.0 5781526 1323 rs1453417 0.688 5781557 1324 rs11039096 0.845 5781753 1325 rs10742793 0.672 5782739 1326 rs11039102 0.704 5783829 1327 rs12279684 0.524 5783893 1328 rs11607346 0.634 5784028 1329 rs6578689 0.71 5784528 1330 rs1453415 0.67 5785595 1331 rs1840175 0.67 5786072 1332 rs4372479 0.655 5792979 1333 rs10734554 0.861 5799485 1334 rs7938541 1.0 5800361 1335 rs4758444 0.524 5802527 1336 rs1979197 0.51 5802898 1337

Example 59

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 43156746 of chromosome 11 was different from those without colorectal cancer (Table 59). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.062 based on permutation analysis, and the corresponding recessive odds ratio is 1.698 (Table 59). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 43156746 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 59 rs no. 890248 Chromosome; Position 11; 43156746 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 1 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 T 720 252 22 Recessive 0.062 1.698 1 T 699 264 37

Table 59A indicates SNPs found to be in strong linkage disequilibrium with rs890248. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 59A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs11601828 0.646 43124098 1338 rs11037302 0.704 43145953 1339 rs7940185 0.669 43149399 1340 rs6485403 0.715 43151108 1341 rs2114089 0.688 43153254 1342 rs7931762 1.0 43154329 1343 rs1559763 1.0 43154718 1344 rs1025168 1.0 43155303 1345 rs1353463 1.0 43156052 1346 rs890249 0.715 43156514 1347 rs890248 — 43156746 1348 rs890246 0.857 43156937 1349 rs7935140 0.715 43158142 1350 rs7938445 1.0 43158508 1351 rs977439 1.0 43159402 1352 rs977438 1.0 43159607 1353 rs7943295 1.0 43160243 1354 rs2068405 1.0 43160762 1355 rs7933421 0.715 43160895 1356 rs959648 1.0 43160975 1357 rs959647 0.715 43161066 1358 rs10838055 0.715 43161471 1359 rs10838056 1.0 43161777 1360 rs7129867 1.0 43161927 1361 rs7950242 1.0 43167395 1362 rs7950144 0.715 43167433 1363 rs1318986 1.0 43169005 1364 rs1025166 1.0 43169462 1365 rs1425857 1.0 43170570 1366 rs10768938 1.0 43171231 1367

Example 60

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 73972614 of chromosome 11 was different from those without colorectal cancer (Table 60). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.007216 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.169 (Table 60). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 73972614 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 60 rs no. 11236164 Chromosome; Position 11; 73972614 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.45469 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 305 618 286 Trend 0.007216 1.169 1 A 267 621 342

Table 60A indicates SNPs found to be in strong linkage disequilibrium with rs11236164. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 60A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs10899009 1.0 73953815 1368 rs10793092 1.0 73956355 1369 rs10793093 0.832 73968600 1370 rs11236164 — 73972614 1371 rs7940880 0.966 73995062 1376 rs10219203 0.96 74002571 1377 rs10793094 1.0 74013473 1383 rs2155935 0.966 74017225 1385 rs2298792 0.966 74017844 1386 rs11236178 0.966 74018984 1387 rs3824999 0.966 74023198 1388 rs10899024 0.705 74036330 1393 rs7932922 0.68 74037678 1396 rs1944933 0.923 74039262 1397 rs11236185 0.928 74040179 1398 rs4145954 0.669 74040814 1399 rs11236187 0.966 74042214 1400 rs11236188 0.966 74042378 1401 rs6421715 0.966 74052598 1402 rs11236203 0.966 74055648 1403 rs11825804 0.964 74056519 1404 rs6592590 0.649 74058677 1405 rs11822234 0.631 74062794 1406 rs11602237 0.604 74063339 1407 rs7104802 0.572 74064448 1408 rs17244949 0.632 74067429 1410

Example 61

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 73982157 of chromosome 11, found within the POLD3 gene, was different from those without colorectal cancer (Table 61). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.038785 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.177 (Table 61). These data further suggest that this marker, located within the POLD3 gene, is associated with colorectal cancer risk and that the C allele at position 73982157 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 61 rs no. 7939226 Chromosome; Position 11; 73982157 Gene Name POLD3 SEQ ID NO; Position 1781; 881 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.59483 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 C 34 322 853 Trend 0.038785 1.177 1 C 25 294 911

Table 61A indicates SNPs found to be in strong linkage disequilibrium with rs7939226. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 61A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs7944514 0.516 73978840 1372 rs7939226 — 73982157 1373 rs10899013 0.543 73987190 1374 rs6592573 0.543 73990610 1375 rs4944051 0.673 74002983 1378 rs4145953 0.66 74009527 1381 rs1433970 0.673 74016841 1384 rs3741127 1.0 74024581 1389 rs1051058 0.673 74029849 1390 rs7123887 0.636 74033737 1391 rs4944922 0.635 74034353 1392 rs7106219 0.636 74036714 1394 rs4944925 0.636 74037177 1395 rs12789086 0.747 74067075 1409 rs11236208 0.707 74067969 1411 rs12282262 0.589 74071586 1412

Example 62

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 74002983 of chromosome 11, found within the POLD3 gene, was different from those without colorectal cancer (Table 62). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.016198 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.176 (Table 62). These data further suggest that this marker, located within the POLD3 gene, is associated with colorectal cancer risk and that the T allele at position 74002983 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 62 rs no. 4944051 Chromosome; Position 11; 74002983 Gene Name POLD3 SEQ ID NO; Position 1781; 21707 Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.12046 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 T 72 406 731 Trend 0.016198 1.176 1 T 53 382 795

Table 62A indicates SNPs found to be in strong linkage disequilibrium with rs4944051. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 62A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs7939226 0.673 73982157 1373 rs4944051 — 74002983 1378 rs7943085 0.582 74007856 1379 rs10501417 0.582 74008628 1380 rs4145953 1.0 74009527 1381 rs11236173 0.582 74009910 1382 rs1433970 1.0 74016841 1384 rs3741127 0.659 74024581 1389 rs1051058 1.0 74029849 1390 rs7123887 0.945 74033737 1391 rs4944922 0.945 74034353 1392 rs7106219 0.945 74036714 1394 rs4944925 0.945 74037177 1395

Example 63

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 83565887 of chromosome 11, found within the DLG2 gene, was different from those without colorectal cancer (Table 63). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.0749 based on permutation analysis, and the corresponding recessive odds ratio is 1.223 (Table 63). These data further suggest that this marker, located within the DLG2 gene, is associated with colorectal cancer risk and that the T allele at position 83565887 of chromosome II is associated with an increased risk of developing colorectal cancer.

TABLE 63 rs no. 1454027 Chromosome; Position 11; 83565887 Gene Name DLG2 SEQ ID NO; Position 1782; 746200 Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.15576 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 T 8 210 771 Recessive 0.0749 1.223 1 T 13 174 809

Table 63A indicates SNPs found to be in strong linkage disequilibrium with rs1454027. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 63A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs790367 0.536 83325571 1413 rs1599914 0.536 83326348 1414 rs790372 0.536 83331489 1415 rs1471687 0.608 83333982 1416 rs790351 0.536 83338726 1417 rs2449592 0.536 83346857 1418 rs2449594 0.536 83359180 1419 rs2514171 0.536 83378990 1420 rs2449575 0.536 83383578 1421 rs1817515 0.536 83385447 1422 rs7933909 0.535 83386501 1423 rs1483387 0.536 83387013 1424 rs1586143 0.536 83389630 1425 rs1118277 0.509 83389983 1426 rs1304480 0.536 83390829 1427 rs2170707 0.536 83400665 1428 rs1483388 0.536 83402660 1429 rs2514167 0.536 83403491 1430 rs2514166 0.536 83403720 1431 rs10751101 0.536 83404929 1432 rs2853026 0.536 83418135 1433 rs1601094 0.536 83420693 1434 rs1160818 0.536 83430317 1435 rs7114261 0.774 83504794 1436 rs7108582 0.774 83508907 1437 rs1945828 0.774 83513418 1438 rs1945824 0.749 83523059 1439 rs10501555 0.774 83525615 1440 rs1014066 0.774 83527163 1441 rs2000961 0.773 83532440 1442 rs1584854 0.536 83540697 1443 rs1598073 0.536 83542042 1444 rs1454019 0.773 83548041 1445 rs1869472 1.0 83555723 1446 rs1454027 — 83565887 1447 rs970226 1.0 83569470 1448 rs1670685 0.536 83570172 1449 rs7943267 0.891 83572107 1450 rs988322 1.0 83574800 1451 rs1377746 1.0 83576676 1452 rs7941004 0.881 83594342 1453 rs10751106 0.73 83597820 1454 rs7394840 1.0 83598063 1455 rs4944472 0.785 83599752 1456 rs10751109 0.774 83601427 1457

Example 64

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 115738853 of chromosome 11 was different from those without colorectal cancer (Table 64). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.006275 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.202 (Table 64). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 115738853 of chromosome 11 is associated with an increased risk of developing colorectal cancer.

TABLE 64 rs no. 572619 Chromosome; Position 11; 115738853 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.94522 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 135 452 384 Trend 0.006275 1.202 1 A 110 437 449

Table 64A indicates SNPs found to be in strong linkage disequilibrium with rs572619. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 64A Linked SNPs SNP r² Position on chr11 SEQ ID NO rs513935 0.507 115737050 1458 rs572619 — 115738853 1459 rs574529 1.0 115739067 1460 rs526151 0.575 115741985 1461 rs571139 0.928 115742227 1462 rs488435 0.575 115742992 1463 rs491111 0.927 115743244 1464 rs567559 0.648 115744952 1465 rs541874 0.615 115745463 1466 rs11215905 0.544 115747903 1467

Example 65

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 9814118 of chromosome 12 was different from those without colorectal cancer (Table 65). The dominant test for risk associated with carrying the A allele had an empirical p-value based on permutation analysis of 0.006667, and the corresponding dominant odds ratio is 1.277 (Table 65). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 9814118 of chromosome 12 is associated with an increased risk of developing colorectal cancer.

TABLE 65 rs no. 724667 Chromosome; Position 12; 9814118 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.09590 Odds Case Flag Allele B AA AB BB Model p-Value Ratio 0 A 563 359 75 Dominant 0.006667 1.277 1 A 503 424 71

Table 65A indicates SNPs found to be in strong linkage disequilibrium with rs724667. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 65A Linked SNPs SNP r² Position on chr12 SEQ ID NO rs3176789 0.959 9803997 1468 rs2071647 1.0 9805272 1469 rs3136559 1.0 9807907 1470 rs3176776 0.64 9808088 1471 rs3176775 0.64 9808349 1472 rs3176773 0.597 9809369 1473 rs12422685 0.64 9811239 1474 rs724668 1.0 9814096 1475 rs724667 — 9814118 1476 rs724666 1.0 9814380 1477 rs10772132 1.0 9816179 1478 rs1029992 1.0 9817025 1479 rs1029991 1.0 9817331 1480 rs1029990 1.0 9817664 1481 rs10844749 1.0 9817891 1482 rs1540356 1.0 9818051 1483 rs12582052 1.0 9818837 1484 rs1861090 0.921 9820946 1485

Example 66

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 31141128 of chromosome 12, found within the DDX11 gene, was different from those without colorectal cancer (Table 66). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.025417 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.139 (Table 66). These data further suggest that this marker, located within the DDX11 gene, is associated with colorectal cancer risk and that the G allele at position 31141128 of chromosome 12 is associated with an increased risk of developing colorectal cancer.

TABLE 66 rs no. 2075322 Chromosome; Position 12; 31141128 Gene Name DDX11 SEQ ID NO; Position 1783; 23052 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.48386 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 G 378 582 243 Trend 0.025417 1.139 1 G 336 617 277

Table 66A indicates SNPs found to be in strong linkage disequilibrium with rs2075322. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 66A Linked SNPs SNP r² Position on chr12 SEQ ID NO rs2075322 — 31141128 1488

Example 67

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 31157554 of chromosome 12 was different from those without colorectal cancer (Table 67). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.027702 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.146 (Table 67). These data further suggest that this marker is associated with colorectal cancer risk and that the A allele at position 31157554 of chromosome 12 is associated with an increased risk of developing colorectal cancer.

TABLE 67 rs no. 4931434 Chromosome; Position 12; 31157554 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.89691 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 538 539 132 Trend 0.027702 1.146 1 A 496 577 157

Table 67A indicates SNPs found to be in strong linkage disequilibrium with rs4931434. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 67A Linked SNPs SNP r² Position on chr12 SEQ ID NO rs11051239 0.534 31132974 1486 rs1808348 0.515 31136113 1487 rs4931432 0.588 31144153 1489 rs11219 0.588 31148962 1490 rs1974752 0.588 31149995 1491 rs2111770 0.581 31152638 1492 rs2005900 0.588 31152965 1493 rs1053552 0.588 31156037 1494 rs4931434 — 31157554 1495 rs4244856 0.581 31157580 1496

Example 68

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 21875373 of chromosome 13 was different from those without colorectal cancer (Table 68). The dominant test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.01544, and the corresponding dominant odds ratio is 1.618 (Table 68). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 21875373 of chromosome 13 is associated with an increased risk of developing colorectal cancer.

TABLE 68 rs no. 10507308 Chromosome; Position 13; 21875373 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.41148 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 G 954 44 1 Dominant 0.01544 1.618 1 G 930 70 1

Table 68A indicates SNPs found to be in strong linkage disequilibrium with rs10507308. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 68A Linked SNPs SNP r² Position on chr13 SEQ ID NO rs9506845 0.66 21846344 1497 rs2038713 1.0 21860220 1498 rs692783 0.59 21868669 1499 rs573671 0.589 21868693 1500 rs1886088 0.59 21870958 1501 rs9316962 0.59 21873258 1502 rs10507308 — 21875373 1503

Example 69

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 32659011 of chromosome 13, found within the STARD13 gene, was different from those without colorectal cancer (Table 69). The trend test for risk associated with carrying the A allele had an empirical p-value of 0.005337 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.229 (Table 69). These data further suggest that this marker, located within the STARD13 gene, is associated with colorectal cancer risk and that the A allele at position 32659011 of chromosome 13 is associated with an increased risk of developing colorectal cancer.

TABLE 69 rs no. 797206 Chromosome; Position 13; 32659011 Gene Name STARD13 SEQ ID NO; Position 1784; 98882 Genotype; Phenotype n = A; increased risk Hardy-Weinberg 0.75076 Case Flag Allele B AA AB BB Model p-Value Odds Ratio 0 A 74 396 500 Trend 0.005337 1.229 1 A 58 365 573

Table 69A indicates SNPs found to be in strong linkage disequilibrium with rs797206. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 69A Linked SNPs SNP r² Position on chr13 SEQ ID NO rs797227 0.68 32643593 1504 rs797222 0.68 32647970 1505 rs797211 0.636 32655052 1506 rs797208 0.951 32658737 1507 rs797206 — 32659011 1508 rs797201 0.904 32665137 1509

Example 70

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 45440577 of chromosome 13, found within the KIAA0853 gene, was different from those without colorectal cancer (Table 70). The dominant test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.023626, and the corresponding dominant odds ratio is 1.210 (Table 70). These data further suggest that this marker, located within the KIAA0853 gene, is associated with colorectal cancer risk and that the G allele at position 45440577 of chromosome 13 is associated with an increased risk of developing colorectal cancer.

TABLE 70 rs no. 4941537 Chromosome; Position 13; 45440577 Gene Name KIAA0853 SEQ ID NO; Position 1785; 84319 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.11382 Case Odds Flag Allele B AA AB BB Model p-Value Ratio 0 G 473 545 190 Dominant 0.023626 1.210 1 G 427 605 198

Table 70A indicates SNPs found to be in strong linkage disequilibrium with rs4941537. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 70A Linked SNPs SNP r² Position on chr13 SEQ ID NO rs7325308 1.0 45412663 1510 rs2075427 1.0 45413606 1511 rs1080107 0.733 45414960 1512 rs6561274 1.0 45416097 1513 rs9534258 1.0 45418874 1514 rs4460970 1.0 45438294 1515 rs4941537 — 45440577 1516 rs9534265 1.0 45445023 1517 rs4942460 1.0 45448444 1518 rs9316177 0.962 45459812 1519 rs9534272 1.0 45464824 1520 rs4941538 1.0 45484610 1521 rs1409436 0.926 45512651 1522 rs3783200 0.744 45514463 1523 rs1087 0.636 45525440 1524 rs9534304 0.568 45538603 1525 rs9526136 0.642 45539148 1526 rs9316179 0.578 45539467 1527 rs9316180 0.578 45539686 1528 rs9562635 0.591 45540993 1530 rs7988836 0.655 45541374 1531 rs7993537 0.578 45541562 1532 rs9534307 0.578 45542131 1533 rs9526140 0.578 45542153 1534 rs9316181 0.578 45543741 1535 rs1409434 0.578 45544445 1536 rs3742264 0.601 45546095 1537 rs9567613 0.578 45547399 1538 rs11618062 0.578 45547569 1539 rs9534312 0.578 45548220 1540 rs9567615 0.607 45549081 1541 rs9567618 0.578 45549309 1542 rs1326398 0.523 45550691 1543 rs723391 0.555 45553450 1544 rs9534322 0.509 45568003 1545 rs1952187 0.524 45572910 1546

Example 71

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 45525440 of chromosome 13, found within the KIAA0853 gene, was different from those without colorectal cancer (Table 71). The trend test for risk associated with carrying the T allele had an empirical p-value of 0.00737 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.181 (Table 71). These data further suggest that this marker, located within the KIAA0853 gene, is associated with colorectal cancer risk and that the T allele at position 45525440 of chromosome 13 is associated with an increased risk of developing colorectal cancer.

TABLE 71 rs no. 1087 Chromosome; Position 13; 45525440 Gene Name KIAA0853 SEQ ID NO; Position 1785; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.42878 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 T 563 515 131 Trend 0.00737 1.181 1 T 507 564 158

Table 71A indicates SNPs found to be in strong linkage disequilibrium with rs1087. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 71A Linked SNPs SNP r² Position on chr13 SEQ ID NO rs7325308 0.636 45412663 1510 rs2075427 0.636 45413606 1511 rs6561274 0.636 45416097 1513 rs9534258 0.636 45418874 1514 rs4460970 0.666 45438294 1515 rs4941537 0.636 45440577 1516 rs9534265 0.613 45445023 1517 rs4942460 0.636 45448444 1518 rs9316177 0.607 45459812 1519 rs9534272 0.634 45464824 1520 rs4941538 0.636 45484610 1521 rs1409436 0.577 45512651 1522 rs3783200 0.744 45514463 1523 rs1087 — 45525440 1524 rs9534304 0.96 45538603 1525 rs9526136 0.957 45539148 1526 rs9316179 0.961 45539467 1527 rs9316180 0.961 45539686 1528 rs9534305 0.724 45540157 1529 rs9562635 0.958 45540993 1530 rs7988836 0.917 45541374 1531 rs7993537 0.961 45541562 1532 rs9534307 0.961 45542131 1533 rs9526140 0.961 45542153 1534 rs9316181 0.961 45543741 1535 rs1409434 0.961 45544445 1536 rs3742264 0.961 45546095 1537 rs9567613 0.961 45547399 1538 rs11618062 0.961 45547569 1539 rs9534312 0.961 45548220 1540 rs9567615 0.956 45549081 1541 rs9567618 0.961 45549309 1542 rs1326398 0.885 45550691 1543 rs723391 0.85 45553450 1544 rs1952187 0.811 45572910 1546

Example 72

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 67187174 of chromosome 14, found within the ARG2 gene, was different from those without colorectal cancer (Table 72). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.005073 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.501 (Table 72). These data further suggest that this marker, located within the ARG2 gene, is associated with colorectal cancer risk and that the C allele at position 67187174 of chromosome 14 is associated with an increased risk of developing colorectal cancer.

TABLE 72 rs no. 10483802 Chromosome; Position 14; 67187174 Gene Name ARG2 SEQ ID NO; Position 1786; 30766 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 1 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 901 69 1 Trend 0.005073 1.501 1 C 890 99 6

Table 72A indicates SNPs found to be in strong linkage disequilibrium with rs10483802. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 72A Linked SNPs SNP r² Position on chr14 SEQ ID NO rs12436474 1.0 67170429 1547 rs8010798 1.0 67184920 1548 rs10483802 — 67187174 1549 rs15493 1.0 67187885 1550 rs1804799 1.0 67188117 1551 rs17249563 0.743 67194680 1552 rs12435927 1.0 67197723 1553 rs8013234 1.0 67219687 1554 rs3759768 1.0 67233546 1555 rs12434923 1.0 67239521 1556 rs12435352 1.0 67241643 1557 rs2009590 0.744 67257453 1558 rs12431676 0.744 67258104 1559 rs910315 0.743 67258676 1560 rs718213 1.0 67266474 1561 rs17836863 1.0 67276155 1562

Example 73

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 46146164 of chromosome 15 was different from those without colorectal cancer (Table 73). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.001698 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.230 (Table 73). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 46146164 of chromosome 15 is associated with an increased risk of developing colorectal cancer.

TABLE 73 rs no. 2469583 Chromosome; Position 15; 46146164 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.60186 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 184 486 297 Trend 0.001698 1.230 1 C 150 476 363

Table 73A indicates SNPs found to be in strong linkage disequilibrium with rs2469583. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 73A Linked SNPs SNP r² Position on chr15 SEQ ID NO rs17423970 0.706 46089356 1563 rs2081619 0.964 46101819 1564 rs17424213 0.965 46103228 1565 rs11070622 0.965 46108382 1566 rs1869453 0.965 46111620 1567 rs1426656 0.965 46114468 1568 rs17340116 0.965 46114858 1569 rs1453857 0.965 46116200 1570 rs1453856 0.965 46116311 1571 rs12324567 0.965 46116717 1572 rs748848 0.965 46118326 1573 rs930016 0.962 46118529 1574 rs930017 0.965 46118841 1575 rs1453855 0.965 46120302 1576 rs1025199 1.0 46126798 1577 rs11070623 1.0 46136739 1578 rs2433363 1.0 46139544 1579 rs1426655 0.964 46145643 1580 rs2469583 — 46146164 1581 rs2469581 0.964 46149357 1582

Example 74

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 93233505 of chromosome 15 was different from those without colorectal cancer (Table 74). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.00088 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.280 (Table 74). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 93233505 of chromosome 15 is associated with an increased risk of developing colorectal cancer.

TABLE 74 rs no. 4372639 Chromosome; Position 15; 93233505 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.44578 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 66 364 570 Trend 0.00088 1.280 1 C 43 321 636

Table 74A indicates SNPs found to be in strong linkage disequilibrium with rs4372639. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 74A Linked SNPs SNP r² Position on chr15 SEQ ID NO rs6496053 0.795 93195638 1583 rs12439498 0.681 93202040 1584 rs4984579 1.0 93217814 1585 rs4489958 1.0 93221398 1586 rs6416529 1.0 93222123 1587 rs4247091 0.919 93226669 1588 rs6496059 1.0 93229804 1589 rs6496060 1.0 93231817 1590 rs6496061 1.0 93232312 1591 rs4372639 — 93233505 1592 rs766233 0.742 93238457 1593 rs12440481 1.0 93261273 1594 rs4306453 0.947 93263139 1595 rs4247087 1.0 93264699 1596 rs1562628 1.0 93265029 1597 rs6496067 1.0 93266435 1598 rs6496068 1.0 93266453 1599 rs11630913 1.0 93267466 1600 rs4283178 0.649 93274496 1601 rs9920787 0.649 93277598 1602 rs6416531 0.569 93279847 1603

Example 75

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 97282996 of chromosome 15, found within the IGF1R gene, was different from those without colorectal cancer (Table 75). The recessive test for risk associated with carrying the C allele had an empirical p-value of 0.0658 based on permutation analysis, and the corresponding recessive odds ratio is 1.311 (Table 75). These data further suggest that this marker, located within the IGF1R gene, is associated with colorectal cancer risk and that the C allele at position 97282996 of chromosome 15 is associated with an increased risk of developing colorectal cancer.

TABLE 75 rs no. 3743262 Chromosome; Position 15; 97282996 Gene Name IGF1R SEQ ID NO; Position 1787; 272709 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 1 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 3 119 1087 Recessive 0.0658 1.311 1 C 6  91 1133

Table 75A indicates SNPs found to be in strong linkage disequilibrium with rs3743262. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 75A Linked SNPs SNP r² Position on chr15 SEQ ID NO rs3743262 — 97282996 1604

Example 76

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 99773203 of chromosome 15, found within the PCSK6 gene, was different from those without colorectal cancer (Table 76). The dominant test for risk associated with carrying the T allele had an empirical p-value based on permutation analysis of 0.003898, and the corresponding dominant odds ratio is 1.673 (Table 76). These data further suggest that this marker, located within the PCSK6 gene, is associated with colorectal cancer risk and that the T allele at position 99773203 of chromosome 15 is associated with an increased risk of developing colorectal cancer.

TABLE 76 rs no. 1994967 Chromosome; Position 15; 99773203 Gene Name PCSK6 SEQ ID NO; Position 1788; 74508 Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.24094 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 T 88 383 499 Dominant 0.003898 1.673 1 T 56 391 548

Table 76A indicates SNPs found to be in strong linkage disequilibrium with rs1994967. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 76A Linked SNPs SNP r² Position on chr15 SEQ ID NO rs1532364 0.81 99768367 1605 rs1000914 0.81 99768456 1606 rs1108993 0.81 99768718 1607 rs880452 0.81 99769785 1608 rs7172235 1.0 99772560 1609 rs12437488 1.0 99772834 1610 rs12912500 1.0 99773041 1611 rs1994967 — 99773203 1612 rs1994968 0.554 99773242 1613 rs4965856 1.0 99775105 1614 rs4965857 1.0 99775156 1615 rs12911482 1.0 99775985 1616 rs2277585 0.515 99785607 1617

Example 77

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 5830572 of chromosome 16 was different from those without colorectal cancer (Table 77). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.000314 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.332 (Table 77). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 5830572 of chromosome 16 is associated with an increased risk of developing colorectal cancer.

TABLE 77 rs no. 7200548 Chromosome; Position 16; 5830572 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.85932 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 G 53 353 565 Trend 0.000314 1.332 1 G 34 308 654

Table 77A indicates SNPs found to be in strong linkage disequilibrium with rs7200548. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 77A Linked SNPs SNP r² Position on chr16 SEQ ID NO rs7187057 0.523 5806139 1618 rs7189118 0.513 5806149 1619 rs1865820 0.509 5806269 1620 rs7189684 0.509 5806460 1621 rs7195375 0.509 5807386 1622 rs11648254 0.573 5807689 1623 rs6500727 0.532 5808267 1624 rs2342743 0.507 5808466 1625 rs2342745 0.509 5808524 1626 rs2342747 0.509 5808701 1627 rs2342748 0.509 5808730 1628 rs7200468 0.509 5809618 1629 rs1550137 0.509 5810450 1630 rs2343252 0.509 5812560 1631 rs9930544 0.509 5813426 1632 rs4296263 0.532 5819886 1633 rs2118014 0.812 5828787 1634 rs7200548 — 5830572 1635

Example 78

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 23619426 of chromosome 16, found within the LOC388226 gene, was different from those without colorectal cancer (Table 78). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.005014 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.212 (Table 78). These data further suggest that this marker, located within the LOC388226 gene, is associated with colorectal cancer risk and that the G allele at position 23619426 of chromosome 16 is associated with an increased risk of developing colorectal cancer.

TABLE 78 rs no. 26764 Chromosome; Position 16; 23619426 Gene Name LOC388226 SEQ ID NO; Position 1789; 12897 Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.61714 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 G 635 390 65 Trend 0.005014 1.212 1 G 573 425 87

Table 78A indicates SNPs found to be in strong linkage disequilibrium with rs26764. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 78A Linked SNPs SNP r² Position on chr16 SEQ ID NO rs249856 0.638 23566477 1636 rs249870 0.638 23573679 1637 rs249869 0.566 23574058 1638 rs249867 0.638 23576069 1639 rs34514 0.637 23578098 1640 rs34513 0.551 23579493 1641 rs35586 0.638 23584507 1642 rs35585 0.566 23584612 1643 rs7588 0.638 23588666 1644 rs40076 0.767 23599906 1645 rs35635 0.566 23601271 1646 rs42873 0.637 23602233 1647 rs35634 0.638 23605180 1648 rs26767 0.766 23605958 1649 rs27770 0.638 23609039 1650 rs35633 0.591 23611506 1651 rs26764 — 23619426 1652 rs26763 1.0 23619684 1653 rs26762 1.0 23619949 1654 rs11074570 0.857 23620229 1655

Example 79

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 13110425 of chromosome 17 was different from those without colorectal cancer (Table 79). The dominant test for risk associated with carrying the G allele had an empirical p-value based on permutation analysis of 0.022381, and the corresponding dominant odds ratio is 1.481 (Table 79). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 13110425 of chromosome 17 is associated with an increased risk of developing colorectal cancer.

TABLE 79 rs no. 1963296 Chromosome; Position 17; 13110425 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.24539 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 G 89 393 518 Dominant 0.022381 1.481 1 G 62 399 541

Table 79A indicates SNPs found to be in strong linkage disequilibrium with rs1963296. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 79A Linked SNPs SNP r² Position on chr17 SEQ ID NO rs1963296 — 13110425 1656 rs3886341 1.0 13112831 1657 rs11869275 0.956 13114370 1658 rs7212267 0.955 13117081 1659 rs2188894 0.831 13117504 1660 rs2214260 0.831 13117537 1661

Example 80

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 30908917 of chromosome 17, found within the LOC342618 gene, was different from those without colorectal cancer (Table 80). The trend test for risk associated with carrying the C allele had an empirical p-value of 0.003563 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.251 (Table 80). These data further suggest that this marker, located within the LOC342618 gene, is associated with colorectal cancer risk and that the C allele at position 30908917 of chromosome 17 is associated with an increased risk of developing colorectal cancer.

TABLE 80 rs no. 10512472 Chromosome; Position 17; 30908917 Gene Name LOC342618 SEQ ID NO; Position 1790; 278 Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.07034 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 685 295 20 Trend 0.003563 1.251 1 C 634 328 39

Table 80A indicates SNPs found to be in strong linkage disequilibrium with rs10512472. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 80A Linked SNPs SNP r² Position on chr17 SEQ ID NO rs10512472 — 30908917 1662 rs12940584 0.536 30912424 1663 rs11655098 0.536 30918963 1664 rs1037590 1.0 30926748 1665 rs11656872 0.536 30962717 1666 rs17669281 0.536 30967908 1667 rs17606150 0.536 30967921 1668 rs16971217 1.0 30968168 1669 rs9897552 1.0 30998594 1670 rs12943224 0.536 31001651 1671 rs11652390 0.536 31006594 1672 rs3506 0.536 31011147 1673 rs11654542 0.536 31013421 1674 rs17670584 0.536 31023017 1675 rs17670614 0.536 31023480 1676 rs9907772 1.0 31024741 1677 rs17676508 0.536 31044721 1678 rs17608253 0.536 31050583 1679

Example 81

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 34299961 of chromosome 18 was different from those without colorectal cancer (Table 81). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.015541 based on permutation analysis, and the corresponding recessive odds ratio is 1.770 (Table 81). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 34299961 of chromosome 18 is associated with an increased risk of developing colorectal cancer.

TABLE 81 rs no. 10502694 Chromosome; Position 18; 34299961 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.18482 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 T 641 323 30 Recessive 0.015541 1.770 1 T 608 336 52

Table 81A indicates SNPs found to be in strong linkage disequilibrium with rs10502694. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 81A Linked SNPs SNP r² Position on chr18 SEQ ID NO rs10502692 1.0 34294350 1680 rs12373278 1.0 34294807 1681 rs9954810 1.0 34297013 1682 rs10502694 — 34299961 1683

Example 82

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 64600521 of chromosome 18 was different from those without colorectal cancer (Table 82). The trend test for risk associated with carrying the G allele had an empirical p-value of 0.004534 based on permutation analysis, and the corresponding Mantel-Haenszel odds ratio for trend is 1.945 (Table 82). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 64600521 of chromosome 18 is associated with an increased risk of developing colorectal cancer.

TABLE 82 rs no. 10503122 Chromosome; Position 18; 64600521 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 1 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 G 0 53 947 Trend 0.004534 1.945 1 G 0 28 973

Table 82A indicates SNPs found to be in strong linkage disequilibrium with rs10503122. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 82A Linked SNPs SNP r² Position on chr18 SEQ ID NO rs646985 1.0 64574312 1684 rs17079646 1.0 64575303 1685 rs631470 1.0 64575455 1686 rs1676846 1.0 64577169 1687 rs12458298 1.0 64577779 1688 rs17079657 1.0 64578874 1689 rs679650 1.0 64579596 1690 rs12604145 1.0 64580779 1691 rs17079677 1.0 64584139 1692 rs491835 1.0 64586668 1693 rs12457185 1.0 64588166 1694 rs12454555 1.0 64588368 1695 rs12455204 1.0 64589299 1696 rs12607604 1.0 64591510 1697 rs595015 1.0 64592428 1698 rs607696 1.0 64592919 1699 rs12454311 1.0 64593139 1700 rs11151464 1.0 64595151 1701 rs17079696 1.0 64595371 1702 rs677592 1.0 64596256 1703 rs11151465 1.0 64596392 1704 rs499881 1.0 64596771 1705 rs1676853 1.0 64600350 1706 rs10503122 — 64600521 1707 rs656681 1.0 64601827 1708 rs17079705 1.0 64602989 1709 rs8092610 1.0 64612870 1710 rs17079717 1.0 64618545 1711

Example 83

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 59485642 of chromosome 19 was different from those without colorectal cancer (Table 83). The dominant test for risk associated with carrying the C allele had an empirical p-value based on permutation analysis of 0.000472, and the corresponding dominant odds ratio is 1.401 (Table 83). These data further suggest that this marker is associated with colorectal cancer risk and that the C allele at position 59485642 of chromosome 19 is associated with an increased risk of developing colorectal cancer.

TABLE 83 rs no. 798893 Chromosome; Position 19; 59485642 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = C; increased risk Hardy-Weinberg 0.26927 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 C 628 266 36 Dominant 0.000472 1.401 1 C 567 331 51

Table 83A indicates SNPs found to be in strong linkage disequilibrium with rs798893. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 83A Linked SNPs SNP r² Position on chr19 SEQ ID NO rs383369 0.535 59475942 1712 rs431420 0.583 59483891 1713 rs386000 0.875 59484573 1714 rs398217 0.856 59484850 1715 rs798887 0.937 59485000 1716 rs798893 — 59485642 1717 rs416867 0.883 59488442 1718 rs384116 0.891 59488531 1719 rs103294 0.945 59489660 1720 rs410852 0.619 59492183 1721

Example 84

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 20272988 of chromosome 21 was different from those without colorectal cancer (Table 84). The recessive test for risk associated with carrying the T allele had an empirical p-value of 0.00021 based on permutation analysis, and the corresponding recessive odds ratio is 1.465 (Table 84). These data further suggest that this marker is associated with colorectal cancer risk and that the T allele at position 20272988 of chromosome 21 is associated with an increased risk of developing colorectal cancer.

TABLE 84 rs no. 377685 Chromosome; Position 21; 20272988 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = T; increased risk Hardy-Weinberg 0.31086 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 T 264 515 220 Recessive 0.00021 1.465 1 T 256 452 293

Table 84A indicates SNPs found to be in strong linkage disequilibrium with rs377685. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 84A Linked SNPs SNP r² Position on chr21 SEQ ID NO rs2825896 0.564 20218657 1722 rs2825899 0.571 20222308 1723 rs2825905 0.561 20226492 1724 rs2825910 0.591 20228734 1725 rs12482291 0.591 20232506 1726 rs2825922 0.714 20243479 1727 rs13047152 0.714 20257959 1728 rs12482827 0.714 20261725 1729 rs377685 — 20272988 1730 rs7281221 0.51 20274521 1731 rs2825928 0.522 20274865 1732 rs2825930 1.0 20279236 1733 rs12482714 1.0 20282727 1734 rs2825941 0.966 20308050 1735

Example 85

For individuals with colorectal cancer, the distribution of polymorphic alleles at position 19773582 of chromosome 22 was different from those without colorectal cancer (Table 85). The recessive test for risk associated with carrying the G allele had an empirical p-value of 0.007571 based on permutation analysis, and the corresponding recessive odds ratio is 1.541 (Table 85). These data further suggest that this marker is associated with colorectal cancer risk and that the G allele at position 19773582 of chromosome 22 is associated with an increased risk of developing colorectal cancer.

TABLE 85 rs no. 431319 Chromosome; Position 22; 19773582 Gene Name SEQ ID NO; Position ; Genotype; Phenotype n = G; increased risk Hardy-Weinberg 0.74998 Case Allele Odds Flag B AA AB BB Model p-Value Ratio 0 G 526 402  72 Recessive 0.007571 1.541 1 G 486 409 107

Table 85A indicates SNPs found to be in strong linkage disequilibrium with rs431319. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 85A Linked SNPs SNP r² Position on chr22 SEQ ID NO rs727497 0.598 19751933 1736 rs9613607 0.598 19752848 1737 rs6417766 0.64 19756298 1738 rs6519750 0.566 19756323 1739 rs9608684 0.573 19756976 1740 rs9613641 0.565 19764380 1741 rs444763 0.855 19767837 1742 rs415591 0.855 19769591 1743 rs399401 0.851 19769618 1744 rs933582 0.855 19769950 1745 rs11913109 0.519 19771148 1746 rs11912450 0.519 19771633 1747 rs1210599 1.0 19772588 1748 rs444204 1.0 19772956 1749 rs365421 1.0 19772978 1750 rs367594 1.0 19773492 1751 rs431319 — 19773582 1752 rs448041 1.0 19773965 1753 rs6005623 0.623 19774278 1754 rs9306459 0.632 19774574 1755 rs9608693 0.601 19774735 1756 rs6005625 0.625 19774818 1757 rs5997305 0.625 19775246 1758 rs1210606 0.885 19776791 1759 rs406160 0.963 19778477 1760

TABLE 86 Modifying effect of the estrogen receptor beta rs1256033 polymorphism on the colorectal risk predicting properties of rs10505477 overall (“OR”). Samples from the Ontario Familial Colorectal Cancer Registry Multiplicative effect of each “A” allele in rs10505477 (OR = 1.22, p = 0.00044) Modifying effects of estrogen receptor beta rs1256033 Gene Name: estrogen receptor beta; SEQ ID NO: 1836 C/C C/T or T/T OR = 1.09 p = 0.42; N = 664 OR = 1.31; p = 0.00015; N = 1568 Samples from the Ontario Familial Colorectal Cancer Registry Multiplicative effect of each “A” allele in rs10505477 by gender alone and in combination with the estrogen receptor beta SNP rs1256033 Male Female OR = 1.27; p = 0.005 OR = 1.18; p = 0.044 estrogen receptor beta: rs1256033 estrogen receptor beta: rs1256033 C/C (N = 344) C/T or T/T (N = 772) C/C (N = 303) C/T or T/T (N = 755) OR = 1.16 p = 0.35 OR = 1.33 p = 0.006 OR = 0.97 p = 0.86 OR = 1.29 p = 0.012

Table 86A indicates SNPs found to be in strong linkage disequilibrium with rs1256033. To generate this list, correlation coefficients (r²) were calculated between the index SNP and all neighboring SNPs cited in the January 2007 HapMap data set release. An r² cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage, i.e., a “strong linkage disequilibrium”.

TABLE 86A Linked SNPs SNP r² Position on chr14 SEQ ID NO rs1152591 0.523 63750601 1791 rs1152589 0.582 63753679 1792 rs915057 0.743 63755960 1793 rs1152588 0.803 63757928 1794 rs1152582 0.773 63762383 1795 rs928554 0.735 63763948 1796 rs1152579 0.73 63764840 1797 rs1152578 0.761 63766790 1798 rs1256065 0.752 63768685 1799 rs1256061 0.646 63773346 1800 rs1256059 0.796 63780170 1801 rs1256056 0.803 63782379 1802 rs4365213 0.583 63790017 1803 rs6573549 0.584 63791402 1804 rs12435857 0.579 63793278 1805 rs1256048 0.87 63798033 1806 rs1256045 0.87 63799513 1807 rs1256044 0.87 63803780 1808 rs1256043 0.845 63804035 1809 rs10148269 0.87 63806677 1810 rs1271573 0.868 63807224 1811 rs1256040 1.0 63808147 1812 rs11158536 0.873 63809928 1813 rs1256038 0.867 63810492 1814 rs1256037 0.869 63813054 1815 rs1256036 0.87 63813085 1816 rs1269056 0.87 63813643 1817 rs960069 0.845 63814755 1818 rs960070 0.873 63814932 1819 rs1256033 — 63815152 1820 rs1256031 1.0 63815932 1821 rs1256030 1.0 63816923 1822 rs3783736 0.528 63821125 1823 rs6573553 0.844 63824114 1824 rs1271572 0.93 63831670 1825 rs3020445 0.775 63858397 1826 rs2357479 0.684 63862517 1827 rs1256112 0.595 63884064 1828 rs1256111 0.547 63886152 1829 rs1256110 0.595 63886610 1830 rs10146204 0.52 63888522 1831 rs1256108 0.547 63891973 1832 rs1256107 0.547 63893134 1833 rs1256101 0.547 63899770 1834 rs1256093 0.518 63912505 1835

Another aspect of the invention is a method of diagnosing colorectal cancer in an individual, or determining whether the individual is at altered risk for colorectal cancer, by detecting polymorphism in a subject by treating a tissue sample from the subject with an antibody to a polymorphic genetic variant of the present invention and detecting binding of said antibody. A person of skill in the art would know how to produce such an antibody (see, for instance, Harlow, E. and Lane, eds., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold Spring Harbor). Such antibodies may include, but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′)₂ fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. The present invention also provides an animal model to study colorectal cancer and susceptibility to colorectal cancer. Such studies can be performed using transgenic animals. For example, one can produce transgenic mice, which contain a specific allelic variant of a containing any of the SNPs disclosed herein. These mice can be created, e.g., by replacing their wild-type gene with an allele containing a SNP disclosed herein, or of the corresponding human gene containing such a SNP.

In a preferred embodiment, the present invention provides a transgenic mammalian animal, said animal having cells incorporating a recombinant expression system adapted to express a gene containing a SNP disclosed herein (preferably the human gene containing a SNP disclosed herein). Generally, the recombinant expression system will be stably integrated into the genome of the transgenic animal and will thus be heritable so that the offspring of such a transgenic animal may themselves contain the transgene. Transgenic animals can be engineered by introducing the a nucleic acid molecule containing only the coding portion of the gene into the genome of animals of interest, using standard techniques for producing transgenic animals. Animals that can serve as a target for transgenic manipulation include, without limitation, mice, rats, rabbits, guinea pigs, sheep, goats, pigs, and non-human primates, e.g. baboons, chimpanzees and monkeys. Techniques known in the art to introduce a transgene into such animals include pronucleic microinjection (U.S. Pat. No. 4,873,191); retrovirus-mediated gene transfer into germ lines (e.g. Van der Putten et al. 1985, Proc. Natl. Acad. Sci. USA 82: 6148-6152); gene targeting in embryonic stem cells (Thompson et al., Cell 56 (1989), 313-321); electroporation of embryos and sperm-mediated gene transfer (for a review, see for example, U.S. Pat. No. 4,736,866). For the purpose of the present invention, transgenic animals include those that carry the recombinant molecule only in part of their cells (“mosaic animals”). The molecule can be integrated either as a single transgene, or in concatamers. Selective introduction of a nucleic acid molecule into a particular cell type is also possible by following, for example, the technique of Lasko et al., Proc. Natl. Acad. Sci. USA 89 (1992): 6232-6236. Particular cells could also be targeted for molecular incorporation with tissue-specific enhancers. The expression of the integrated molecule can be monitored by standard techniques such as in situ hybridization, Northern Blot analysis, PCR or immunocytochemistry. Transgenic animals that include a copy of such a nucleic acid molecule introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding the corresponding protein. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.

The present invention has been described in detail by way of illustration and example in order to acquaint others skilled in the art with the invention, its principles and its practical application. Particular formulations and processes of the present invention are not limited to the descriptions of the specific embodiments presented, but rather the descriptions and examples should be viewed in terms of the claims that follow and their equivalents. While some of the examples and descriptions above include some conclusions about the way the invention may function, the inventors do not intend to be bound by those conclusions and functions, but put them forth only as possible explanations.

It is to be further understood that the specific embodiments of the present invention as set forth are not intended as being exhaustive or limiting of the invention, and that many alternatives, modifications and variations will be apparent to those of ordinary skill in the art in light of the foregoing examples and detailed description. Accordingly, this invention is intended to embrace all such alternatives, modifications and variations that fall within the spirit and scope of the following claims.

REFERENCE LIST

All publications mentioned in the specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference herein.

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1. A method for identifying an individual who has an altered risk for developing colorectal cancer, comprising detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases: a base located at position 20805662 to position 21 149959 on human chromosome 1; a base located at position 54531998 to position 54563831 on human chromosome 1; a base located at position 96911594 to position 97159204 on human chromosome 1; a base located at position 97653506 to position 97659904 on human chromosome 1; a base located at position 106818235 to position 107115334 on human chromosome 1; a base located at position 114947052 to position 115303040 on human chromosome 1; a base located at position 114975727 on human chromosome 1; a base located at position 142933600 to position 143043494 on human chromosome 1; a base located at position 20250764 to position 20260227 on human chromosome 2; a base located at position 49157212 to position 49335916 on human chromosome 2; a base located at position 186729521 to position 187050892 on human chromosome 2; a base located at position 218767422 to position 218873288 on human chromosome 2; a base located at position 230822818 to position 230842525 on human chromosome 2; a base located at position 25052936 to position 25121605 on human chromosome 3; a base located at position 25169305 to position 25300483 on human chromosome 3; a base located at position 62937809 to position 62985367 on human chromosome 3; a base located at position 120013362 to position 120044441 on human chromosome 3; a base located at position 120036240 to position 120044441 on human chromosome 3; a base located at position 186008653 to position 186267820 on human chromosome 3; a base located at position 1878431 11 to position 187878274 on human chromosome 3; a base located at position 4846426 to position 4867970 on human chromosome 4; a base located at position 73187634 to position 73501955 on human chromosome 4; a base located at position 156007562 to position 156033905 on human chromosome 4; a base located at position 114716570 to position 114747490 on human chromosome 5; a base located at position 121 110284 on human chromosome 5; a base located at position 128103463 to position 128358774 on human chromosome 5; a base located at position 1026731 to position 1037761 on human chromosome 6; a base located at position 69363616 to position 69521107 on human chromosome 6; a base located at position 82950808 to position 83172329 on human chromosome 6; a base located at position 129960436 to position 129970245 on human chromosome 6; a base located at position 11585877 on human chromosome 7; a base located at position 81554149 to position 81654315 on human chromosome 7; a base located at position 144628286 to position 144819907 on human chromosome 7; a base located at position 149201414 to position 149243724 on human chromosome 7; a base located at position 4252805 to position 4257764 on human chromosome 8; a base located at position 9426711 to position 9673180 on human chromosome 8; a base located at position 55688038 to position 55886453 on human chromosome 8; a base located at position 105447572 on human chromosome 8; a base located at position 128476287 to position 128481192 on human chromosome 8; a base located at position 128476372 to position 128495575 on human chromosome 8; a base located at position 128476372 to position 128500876 on human chromosome 8; a base located at position 128476625 to position 128495575 on human chromosome 8; a base located at position 128477246 to position 128524876 on human chromosome 8; a base located at position 128477298 to position 128495575 on human chromosome 8; a base located at position 128484074 to position 128500876 on human chromosome 8; a base located at position 138448609 to position 138616778 on human chromosome 8; a base located at position 141567935 to position 141597272 on human chromosome 8; a base located at position 6282602 to position 6399874 on human chromosome 9; a base located at position 73606988 to position 73643177 on human chromosome 9; a base located at position 79353007 to position 79359981 on human chromosome 9; a base located at position 110115339 to position 110130428 on human chromosome 9; a base located at position 4430296 to position 4543829 on human chromosome 11; a base located at position 5766124 to position 5802898 on human chromosome 11; a base located at position 43124098 to position 43171231 on human chromosome 11; a base located at position 73953815 to position 74067429 on human chromosome 11; a base located at position 73978840 to position 74071586 on human chromosome 11; a base located at position 73982157 to position 74037177 on human chromosome 11; a base located at position 83325571 to position 83601427 on human chromosome 11; a base located at position 115737050 to position 115747903 on human chromosome 11; a base located at position 9803997 to position 9820946 on human chromosome 12; a base located at position 31132974 to position 31157580 on human chromosome 12; a base located at position 31141128 on human chromosome 12; a base located at position 21846344 to position 21875373 on human chromosome 13; a base located at position 32643593 to position 32665137 on human chromosome 13; a base located at position 45412663 to position 45572910 on human chromosome 13; a base located at position 67170429 to position 67276155 on human chromosome 14; a base located at position 46089356 to position 461-49357 on human chromosome 15; a base located at position 93195638 to position 93279847 on human chromosome 15; a base located at position 97282996 on human chromosome 15; a base located at position 99768367 to position 99785607 on human chromosome 15; a base located at position 5806139 to position 5830572 on human chromosome 16; a base located at position 23566477 to position 23620229 on human chromosome 16; a base located at position 13110425 to position 13117537 on human chromosome 17; a base located at position 30908917 to position 31050583 on human chromosome 17; a base located at position 34294350 to position 34299961 on human chromosome 18; a base located at position 64574312 to position 64618545 on human chromosome 18; a base located at position 59475942 to position 59492183 on human chromosome 19; a base located at position 20218657 to position 20308050 on human chromosome 21; and a base located at position 19751933 to position 19778477 on human chromosome 22; or a base in strong linkage disequilibrium with at least one of the foregoing bases.
 2. The method of claim 1, which comprises detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases: a base located at position 20805662 to position 21149959 on human chromosome 1; a base located at position 54531998 to position 54563831 on human chromosome 1; a base located at position 96911594 to position 97159204 on human chromosome 1; a base located at position 97653506 to position 97659904 on human chromosome 1; a base located at position 106818235 to position 107115334 on human chromosome 1; a base located at position 114947052 to position 115303040 on human chromosome 1; a base located at position 1 14975727 on human chromosome 1; a base located at position 142933600 to position 143043494 on human chromosome 1; a base located at position 20250764 to position 20260227 on human chromosome 2; a base located at position 49157212 to position 49335916 on human chromosome 2; a base located at position 186729521 to position 187050892 on human chromosome 2; a base located at position 218767422 to position 218873288 on human chromosome 2; a base located at position 230822818 to position 230842525 on human chromosome 2; a base located at position 25052936 to position 25121605 on human chromosome 3; a base located at position 25169305 to position 25300483 on human chromosome 3; a base located at position 62937809 to position 62985367 on human chromosome 3; a base located at position 120013362 to position 120044441 on human chromosome 3; a base located at position 120036240 to position 120044441 on human chromosome 3; a base located at position 186008653 to position 186267820 on human chromosome 3; a base located at position 187843111 to position 187878274 on human chromosome 3; a base located at position 4846426 to position 4867970 on human chromosome 4; a base located at position 73187634 to position 73501955 on human chromosome 4; a base located at position 156007562 to position 156033905 on human chromosome 4; a base located at position 114716570 to position 114747490 on human chromosome 5; a base located at position 121110284 on human chromosome 5; a base located at position 128103463 to position 128358774 on human chromosome 5; a base located at position 1026731 to position 1037761 on human chromosome 6; a base located at position 69363616 to position 69521107 on human chromosome 6; a base located at position 82950808 to position 83172329 on human chromosome 6; a base located at position 129960436 to position 129970245 on human chromosome 6; a base located at position 11585877 on human chromosome 7; a base located at position 81554149 to position 81654315 on human chromosome 7; a base located at position 144628286 to position 144819907 on human chromosome 7; a base located at position 149201414 to position 149243724 on human chromosome 7; a base located at position 4252805 to position 4257764 on human chromosome 8; a base located at position 9426711 to position 9673180 on human chromosome 8; a base located at position 55688038 to position 55886453 on human chromosome 8; a base located at position 105447572 on human chromosome 8; a base located at position 128476287 to position 128481192 on human chromosome 8; a base located at position 128476372 to position 128495575 on human chromosome 8; a base located at position 128476372 to position 128500876 on human chromosome 8; a base located at position 128476625 to position 128495575 on human chromosome 8; a base located at position 128477246 to position 128524876 on human chromosome 8; a base located at position 128477298 to position 128495575 on human chromosome 8 a base located at position 128484074 to position 128500876 on human chromosome 8; a base located at position 138448609 to position 138616778 on human chromosome 8; a base located at position 141567935 to position 141597272 on human chromosome 8; a base located at position 6282602 to position 6399874 on human chromosome 9; a base located at position 73606988 to position 73643177 on human chromosome 9; a base located at position 79353007 to position 79359981 on human chromosome 9; a base located at position 110115339 to position 110130428 on human chromosome 9; a base located at position 4430296 to position 4543829 on human chromosome 11; a base located at position 5766124 to position 5802898 on human chromosome 11; a base located at position 43124098 to position 43171231 on human chromosome 11; a base located at position 73953815 to position 74067429 on human chromosome 11; a base located at position 73978840 to position 74071586 on human chromosome 11; a base located at position 73982157 to position 74037177 on human chromosome 11; a base located at position 83325571 to position 83601427 on human chromosome 11; a base located at position 115737050 to position 115747903 on human chromosome 11; a base located at position 9803997 to position 9820946 on human chromosome 12; a base located at position 31132974 to position 31157580 on human chromosome 12; a base located at position 31141128 on human chromosome 12; a base located at position 21846344 to position 21875373 on human chromosome 13; a base located at position 32643593 to position 32665137 on human chromosome 13; a base located at position 45412663 to position 45572910 on human chromosome 13; a base located at position 67170429 to position 67276155 on human chromosome 14; a base located at position 46089356 to position 46149357 on human chromosome 15; a base located at position 93195638 to position 93279847 on human chromosome 15; a base located at position 97282996 on human chromosome 15; a base located at position 99768367 to position 99785607 on human chromosome 15; a base located at position 5806139 to position 5830572 on human chromosome 16; a base located at position 23566477 to position 23620229 on human chromosome 16; a base located at position 13110425 to position 13117537 on human chromosome 17; a base located at position 30908917 to position 31050583 on human chromosome 17; a base located at position 34294350 to position 34299961 on human chromosome 18; a base located at position 64574312 to position 64618545 on human chromosome 18; a base located at position 59475942 to position 59492183 on human chromosome 19; a base located at position 20218657 to position 20308050 on human chromosome 21; and a base located at position 19751933 to position 19778477 on human chromosome 22; or a base in strong linkage disequilibrium with at least one of the foregoing bases.
 3. The method of claim 2, wherein said base is in strong linkage disequilibrium with at least one of the nucleotide bases located as follows: at position 20805662, 20807307, 20812307, 20814435, 20833262, 20834778, 20835387, 20843033, 20843089, 20843172, 20845152, 20851322, 20859722, 20860139, 20866984, 20868329, 20869596, 20871652, 20873726, 20885691, 20890966, 20897686, 20897690, 20897946, 20900501, 20901973, 20902168, 20910482, 20912408, 20922516, 20925487, 20925556, 20927846, 20931914, 20934009, 20935818, 20937929, 20939816, 20943571, 20945070, 20945280, 20945717, 20949204, 20949302, 20951449, 20955075, 20958577, 20959014, 20960041, 20965681, 20965980, 20966007, 20969559, 20972644, 20980229, 20984365, 20986738, 20993250, 20994909, 20997023, 20999899, 21000095, 21000981, 21004018, 21006394, 21010403, 21016114, 21022160, 21024702, 21028251, 21033244, 21035367, 21035826, 21040905, 21041170, 21044669, 21050902, 21051467, 21055398, 21062830, 21063762, 21068091, 21068874, 21069797, 21072609, 21078118, 21082461, 21082628, 21084950, 21101147, 21106482, 21107684, 21112807, 21114874, 21120116, 21120469, 21121210, 21127511, 21131101, 21136620, 21137181, 21140439, 21140663, 21141522, 21141902, 21142192, 21145524, 21149959, 54531998, 54538208, 54548927, 54551090, 54552517, 54556623, 54557621, 54561302, 54561394, 54562638, 54563585, 54563831, 96911594, 96938696, 96961817, 97005044, 97141267, 97159204, 97653506, 97657313, 97659904, 106818235, 106828844, 106830088, 106833215, 106891798, 106912949, 106928115, 106930964, 106937218, 106971827, 106998017, 107004258, 107006719, 107010986, 107011275, 107011305, 107011409, 107011554, 107011627, 107012941, 107014445, 107017707, 107021830, 107024684, 107025142, 107033827, 107034845, 107044596, 107047341, 107048343, 107052637, 107054139, 107056341, 107056364, 107079348, 107080550, 107081508, 107086826, 107088101, 107091984, 107092704, 107093768, 107095587, 107096669, 107098220, 107100885, 107103052, 107112872, 107115313, 107115334, 114947052, 114968711, 114969563, 114975727, 114978348, 114981253, 114984296, 115004020, 115071842, 115073938, 115075249, 115077252, 115081154, 115084567, 115087972, 115091656, 115100040, 115101751, 115103811, 115104443, 115111982, 115116141, 115119103, 115125087, 115127174, 115132157, 115132560, 115132947, 115139005, 115139260, 115141772, 115159909, 115166656, 115167322, 115171216, 115179531, 115180386, 115182953, 115183282, 115185601, 115193640, 115200356, 115202960, 115209101, 115217819, 115226640, 115234779, 115236258, 115242333, 115242502, 115242740, 115244057, 115261728, 115268188, 115277042, 115278233, 115278345, 115278448, 115278686, 115279927, 115280070, 115281663, 115282510, 115282884, 115284407, 115285912, 115287160, 115287345, 115289952, 115292582, 115298443, 115298798, 115303040, 142933600, 142994415, 142996870, 143024965, 143037007, 143039966, 143040559, or 143043494 on human chromosome 1; at position 20250764, 20250981, 20252966, 20254115, 20254650, 20255588, 20256013, 20257476, 20258973, 20259648, 20260227, 49157212, 49163446, 49169518, 49180455, 49183068, 49184463, 49185265, 49186995, 49187513, 49187893, 49189474, 49189694, 49190619, 49191171, 49191484, 49192006, 49195881, 49199434, 49199611, 49199634, 49199711, 49203878, 49204013, 49204336, 49205020, 49205539, 49205989, 49227109, 49239677, 49239769, 49242500, 49242583, 49244528, 49253703, 49311997, 49319087, 49329514, 49329682, 49332061, 49332761, 49335916, 186729521, 186748482, 186752544, 186753368, 186759677, 186771130, 186774634, 186783677, 186788675, 186795981, 186797056, 186797101, 186804008, 186822924, 186841731, 186849447, 186854278, 186854406, 186856196, 186866149, 186869233, 186869364, 186870116, 186873391, 186873805, 186874321, 186876760, 186877596, 186878043, 186883056, 186887466, 186891840, 186892009, 186895423, 186897281, 186898014, 186899824, 186903194, 186905158, 186910195, 186918596, 186918660, 186933341, 186935034, 186937617, 186938372, 186938761, 186940537, 186942136, 186944471, 186945120, 186950816, 187032899, 187050892, 218767422, 218767819, 218767857, 218768482, 218770121, 218770314, 218770551, 218771180, 218773021, 218776751, 218777739, 218781315, 218784326, 218786186, 218789557, 218791821, 218803037, 218814280, 218816511, 218823086, 218826240, 218830515, 218832566, 218833258, 218833506, 218833898, 218835652, 218846420, 218852394, 218852478, 218871943, 218873288, 230822818, 230822908, 230823742, 230824051, 230824308, 230824428, 230825316, 230825613, 230825727, 230825877, 230827852, 230828862, 230829298, 230830081, 230830316, 230830886, 230832540, 230838320, or 230842525 on human chromosome 2; at position 25052936, 25054402, 25056885, 25061156, 25062781, 25068060, 25076452, 25084253, 25084806, 25086476, 25090198, 25090417, 25091862, 25093457, 25099388, 25100369, 25102693, 25105990, 25108277, 25112900, 25114656, 25115540, 25117575, 25118394, 25121605, 25169305, 25170688, 25184366, 25188663, 25194200, 25205423, 25207827, 25211158, 25211837, 25235457, 25238040, 25239011, 25239845, 25243914, 25244762, 25244932, 25245547, 25250478, 25264520, 25265009, 25269521, 25273091, 25273425, 25274083, 25275052, 25277488, 25279386, 25280012, 25280571, 25283486, 25283965, 25284812, 25285067, 25287098, 25287161, 25288171, 25291318, 25291410, 25295964, 25300483, 62937809, 62941462, 62943033, 62943151, 62943547, 62945427, 62949979, 62952892, 62955440, 62957942, 62958060, 62959133, 62959399, 62960430, 62961266, 62962215, 62964393, 62965607, 62966446, 62966549, 62968123, 62968779, 62968976, 62969677, 62970029, 62970190, 62970589, 62971291, 62972138, 62975188, 62981633, 62982901, 62983787, 62985367, 120013362, 120013382, 120036240, 120037273, 120037336, 120037804, 120039183, 120039851, 120044441, 186008653, 186008673, 186008910, 186012692, 186027445, 186032241, 186033203, 186038166, 186041770, 186043671, 186049741, 186052729, 186056257, 186058136, 186058533, 186059022, 186060619, 186063619, 186070576, 186070838, 186072802, 186073295, 186076934, 186079782, 186081364, 186083378, 186090182, 186099834, 186104572, 186112996, 186113805, 186115949, 186117351, 186119962, 186126928, 186131728, 186142625, 186146360, 186148006, 186149057, 186152026, 186156901, 186244971, 186252104, 186267820, 187843111, 187857373, 187860431, 187873329, or 187878274 on human chromosome 3; at position 4846426, 4857130, 4857759, 4862109, 4867970, 73187634, 73200067, 73328055, 73346262, 73346848, 73348223, 73357454, 73363372, 73365920, 73368604, 73376981, 73386336, 73387894, 73401936, 73402263, 73403367, 73409745, 73418036, 73418955, 73419931, 73420592, 73420874, 73420904, 73420954, 73421198, 73421361, 73421626, 73421636, 73424191, 73426574, 73428206, 73428609, 73429022, 73429166, 73429961, 73430864, 73432371, 73432662, 73433172, 73435810, 73435851, 73437550, 73437882, 73438096, 73440758, 73441001, 73441029, 73442206, 73445194, 73446950, 73448534, 73451047, 73453617, 73454336, 73455010, 73456969, 73461427, 73468266, 73468802, 73469693, 73472897, 73473510, 73474331, 73475459, 73476824, 73481968, 73482388, 73484550, 73489468, 73491229, 73491598, 73492707, 73493192, 73493907, 73496343, 73496916, 73501955, 156007562, 156008015, 156009501, 156010845, 156019936, 156020341, 156027459, 156029231, 156030563, 156032538, or 156033905 on human chromosome 4; at position 114716570, 114718052, 114719100, 114719186, 114720973, 114721020, 114724952, 114727927, 114728598, 114729688, 114730035, 114730402, 114731087, 114734391, 114735264, 114735588, 114735981, 114736503, 114737036, 114737354, 114739954, 114741070, 114742706, 114743558, 114743576, 114744950, 114747047, 114747337, 114747490, 121110284, 128103463, 128108152, 128113997, 128120050, 128134369, 128135572, 128139763, 128141175, 128145987, 128146786, 128156553, 128157693, 128160641, 128164258, 128170372, 128197696, 128206257, 128220969, 128223084, 128227979, 128228401, 128232311, 128232320, 128233576, 128233727, 128234493, 128234617, 128234806, 128235438, 128235745, 128235767, 128236078, 128236528, 128238639, 128240119, 128241301, 128258653, 128260778, 128260800, 128263313, 128265259, 128269933, 128271956, 128273703, 128279649, 128280539, 128287628, 128289750, 128316551, 128327389, 128340511, 128341528, 128345166, 128346380, 128348967, 128351543, 128352581, 128352924, 128353107, 128355391, 128355483, 128356081, or 128358774 on human chromosome 5; at position 1026731, 1032864, 1032946, 1033885, 1033964, 1034131, 1034217, 1035056, 1035451, 1037138, 1037761, 69363616, 69379328, 69411039, 69414352, 69414862, 69416925, 69428738, 69429357, 69429728, 69435338, 69435377, 69435704, 69436412, 69437088, 69437132, 69437929, 69439747, 69440936, 69445347, 69447873, 69449271, 69454318, 69455343, 69461590, 69462851, 69463179, 69469800, 69471343, 69483117, 69483590, 69486083, 69490498, 69496298, 69497479, 69504298, 69504487, 69511710, 69513299, 69517615, 69518419, 69521107, 82950808, 83037702, 83052756, 83052893, 83059529, 83059811, 83063355, 83065585, 83065715, 83066965, 83067321, 83079412, 83086171, 83086772, 83087733, 83088471, 83089659, 83092525, 83092537, 83094274, 83094499, 83094576, 83095347, 83095565, 83095939, 83096974, 83097004, 83097222, 83098262, 83098329, 83098352, 83100260, 83101000, 83103870, 83104741, 83105428, 83113039, 83114887, 83120523, 83122607, 83126442, 83127291, 83129590, 83131084, 83137358, 83140060, 83146661, 83147795, 83150543, 83153296, 83155501, 83162032, 83163350, 83165082, 83165771, 83167427, 83167802, 83168404, 83169297, 83169493, 83170215, 83170490, 83170598, 83172329, 129960436, 129960703, 129962477, or 129970245 on human chromosome 6; at position 11585877, 81554149, 81559478, 81559837, 81641687, 81648931, 81654315, 144628286, 144628318, 144628632, 144629754, 144629965, 144630098, 144635813, 144643683, 144645286, 144646697, 144669590, 144669600, 144671926, 144672558, 144674138, 144676045, 144676393, 144678594, 144678612, 144680315, 144718311, 144720727, 144733732, 144733992, 144734180, 144734239, 144734742, 144738529, 144744457, 144745645, 144745774, 144745875, 144751586, 144752182, 144752705, 144753415, 144753565, 144754173, 144755233, 144755604, 144755775, 144756961, 144757255, 144759437, 144760563, 144761726, 144766026, 144766794, 144767960, 144768118, 144768579, 144768715, 144770877, 144770905, 144771574, 144771653, 144771867, 144774486, 144774883, 144776678, 144777538, 144778707, 144781332, 144781771, 144782495, 144783026, 144783666, 144784599, 144785299, 144788902, 144791211, 144793063, 144796105, 144799583, 144799675, 144800213, 144800438, 144800519, 144800830, 144801300, 144802085, 144802576, 144803188, 144803650, 144804012, 144804167, 144805193, 144805467, 144806025, 144806327, 144806354, 144808010, 144810732, 144814121, 144814527, 144818301, 144819907, 149201414, 149210939, 149213761, 149214960, 149219765, 149242026, 149242664, or 149243724 on human chromosome 7; at position 4252805, 4257185, 4257764, 9426711, 9431741, 9436057, 9436101, 9436786, 9437029, 9437099, 9439838, 9440072, 9440613, 9444872, 9452052, 9458679, 9460336, 9463104, 9468129, 9480306, 9503674, 9523873, 9526021, 9526193, 9529470, 9531111, 9538857, 9541393, 9546289, 9549119, 9558649, 9563755, 9568067, 9568084, 9568712, 9640154, 9645506, 9673180, 55688038, 55688723, 55688788, 55689106, 55691506, 55692165, 55698923, 55699691, 55701610, 55704003, 55704066, 55704170, 55714151, 55718398, 55720864, 55724371, 55724624, 55725409, 55729655, 55732233, 55734727, 55734972, 55735628, 55735791, 55736905, 55738068, 55740834, 55741606, 55742554, 55747804, 55748460, 55752508, 55760756, 55761309, 55776456, 55783865, 55801936, 55811566, 55819136, 55821626, 55823685, 55825618, 55845129, 55858095, 55861650, 55870126, 55880446, 55883850, 55886453, 105447572, 128476287, 128476372, 128476625, 128477246, 128477298, 128478414, 128478693, 128481192, 128482329, 128482487, 128483680, 128484074, 128486686, 128487118, 128489299, 128490967, 128492309, 128492523, 128492580, 128492832, 128492999, 128493974, 128495575, 128500876, 128509349, 128512569, 128524876, 138448609, 138448978, 138450507, 138450935, 138451287, 138452272, 138452507, 138452835, 138453471, 138454113, 138454197, 138454235, 138454833, 138455486, 138455728, 138456184, 138456296, 138456395, 138457265, 138458205, 138458287, 138458607, 138459228, 138459736, 138460258, 138460320, 138460491, 138461455, 138461471, 138461926, 138462319, 138467267, 138467277, 138467539, 138469853, 138469883, 138472916, 138473941, 138477490, 138481482, 138482393, 138490184, 138498734, 138545196, 138546484, 138551497, 138576626, 138578139, 138580074, 138583352, 138585809, 138585968, 138586498, 138588282, 138590203, 138590751, 138594903, 138598108, 138601596, 138601771, 138603600, 138603658, 138603708, 138604408, 138604979, 138607006, 138607169, 138607178, 138608732, 138610100, 138610110, 138610517, 138611185, 138611655, 138611699, 138611757, 138612308, 138614096, 138614490, 138614687, 138615037, 138615093, 138615852, 138616621, 138616711, 138616778, 141567935, 141583366, 141587219, 141589763, 141595220, 141595413, 141596167, 141596488, or 141597272 on human chromosome 8; at position 6282602, 6291578, 6299862, 6300908, 6314376, 6316825, 6321421, 6321610, 6322901, 6325760, 6332328, 6340235, 6341111, 6341834, 6342819, 6349144, 6352365, 6354449, 6354533, 6355614, 6355683, 6375637, 6385247, 6385540, 6386245, 6390030, 6392856, 6397799, 6397843, 6398247, 6399874, 73606988, 73607164, 73607569, 73612124, 73613027, 73614943, 73615076, 73615232, 73616781, 73617303, 73618675, 73619146, 73622095, 73622395, 73622439, 73625852, 73626601, 73626706, 73627824, 73628740, 73629704, 73633747, 73634385, 73635467, 73635691, 73635782, 73636447, 73636612, 73636831, 73638980, 73639771, 73639895, 73640222, 73642109, 73642315, 73643177, 79353007, 79353924, 79356465, 79356737, 79359981, 110115339, or 110130428 on human chromosome 9; at position 4430296, 4430392, 4430569, 4434860, 4440254, 4442501, 4443277, 4443753, 4444427, 4444806, 4446686, 4448408, 4449042, 4449105, 4449910, 4450407, 4450528, 4451604, 4453189, 4453422, 4453492, 4453537, 4453673, 4454017, 4454894, 4532655, 4543829, 5766124, 5766249, 5766322, 5768065, 5772861, 5774897, 5775192, 5776193, 5778275, 5779169, 5779183, 5779725, 5779774, 5779871, 5780048, 5780227, 5781044, 5781459, 5781526, 5781557, 5781753, 5782739, 5783829, 5783893, 5784028, 5784528, 5785595, 5786072, 5792979, 5799485, 5800361, 5802527, 5802898, 43124098, 43145953, 43149399, 43151108, 43153254, 43154329, 43154718, 43155303, 43156052, 43156514, 43156746, 43156937, 43158142, 43158508, 43159402, 43159607, 43160243, 43160762, 43160895, 43160975, 43161066, 43161471, 43161777, 43161927, 43167395, 43167433, 43169005, 43169462, 43170570, 43171231, 73953815, 73956355, 73968600, 73972614, 73978840, 73982157, 73987190, 73990610, 73995062, 74002571, 74002983, 74007856, 74008628, 74009527, 74009910, 74013473, 74016841, 74017225, 74017844, 74018984, 74023198, 74024581, 74029849, 74033737, 74034353, 74036330, 74036714, 74037177, 74037678, 74039262, 74040179, 74040814, 74042214, 74042378, 74052598, 74055648, 74056519, 74058677, 74062794, 74063339, 74064448, 74067075, 74067429, 74067969, 74071586, 83325571, 83326348, 83331489, 83333982, 83338726, 83346857, 83359180, 83378990, 83383578, 83385447, 83386501, 83387013, 83389630, 83389983, 83390829, 83400665, 83402660, 83403491, 83403720, 83404929, 83418135, 83420693, 83430317, 83504794, 83508907, 83513418, 83523059, 83525615, 83527163, 83532440, 83540697, 83542042, 83548041, 83555723, 83565887, 83569470, 83570172, 83572107, 83574800, 83576676, 83594342, 83597820, 83598063, 83599752, 83601427, 115737050, 115738853, 115739067, 115741985, 115742227, 115742992, 115743244, 115744952, 115745463, or 115747903 on human chromosome 11; at position 9803997, 9805272, 9807907, 9808088, 9808349, 9809369, 9811239, 9814096, 9814118, 9814380, 9816179, 9817025, 9817331, 9817664, 9817891, 9818051, 9818837, 9820946, 31132974, 31136113, 31141128, 31144153, 31148962, 31149995, 31152638, 31152965, 31156037, 31157554, or 31157580 on human chromosome 12; at position 21846344, 21860220, 21868669, 21868693, 21870958, 21873258, 21875373, 32643593, 32647970, 32655052, 32658737, 32659011, 32665137, 45412663, 45413606, 45414960, 45416097, 45418874, 45438294, 45440577, 45445023, 45448444, 45459812, 45464824, 45484610, 45512651, 45514463, 45525440, 45538603, 45539148, 45539467, 45539686, 45540157, 45540993, 45541374, 45541562, 45542131, 45542153, 45543741, 45544445, 45546095, 45547399, 45547569, 45548220, 45549081, 45549309, 45550691, 45553450, 45568003, or 45572910 on human chromosome 13; at position 67170429, 67184920, 67187174, 67187885, 67188117, 67194680, 67197723, 67219687, 67233546, 67239521, 67241643, 67257453, 67258104, 67258676, 67266474, or 67276155 on human chromosome 14; at position 46089356, 46101819, 46103228, 46108382, 46111620, 46114468, 46114858, 46116200, 46116311, 46116717, 46118326, 46118529, 46118841, 46120302, 46126798, 46136739, 46139544, 46145643, 46146164, 46149357, 93195638, 93202040, 93217814, 93221398, 93222123, 93226669, 93229804, 93231817, 93232312, 93233505, 93238457, 93261273, 93263139, 93264699, 93265029, 93266435, 93266453, 93267466, 93274496, 93277598, 93279847, 97282996, 99768367, 99768456, 99768718, 99769785, 99772560, 99772834, 99773041, 99773203, 99773242, 99775105, 99775156, 99775985, or 99785607 on human chromosome 15; at position 5806139, 5806149, 5806269, 5806460, 5807386, 5807689, 5808267, 5808466, 5808524, 5808701, 5808730, 5809618, 5810450, 5812560, 5813426, 5819886, 5828787, 5830572, 23566477, 23573679, 23574058, 23576069, 23578098, 23579493, 23584507, 23584612, 23588666, 23599906, 23601271, 23602233, 23605180, 23605958, 23609039, 23611506, 23619426, 23619684, 23619949, or 23620229 on human chromosome 16; at position 13110425, 131 12831, 13114370, 13117081, 13117504, 13117537, 30908917, 30912424, 30918963, 30926748, 30962717, 30967908, 30967921, 30968168, 30998594, 31001651, 31006594, 31011147, 31013421, 31023017, 31023480, 31024741, 31044721, or 31050583 on human chromosome 17; at position 34294350, 34294807, 34297013, 34299961, 64574312, 64575303, 64575455, 64577169, 64577779, 64578874, 64579596, 64580779, 64584139, 64586668, 64588166, 64588368, 64589299, 64591510, 64592428, 64592919, 64593139, 64595151, 64595371, 64596256, 64596392, 64596771, 64600350, 64600521, 64601827, 64602989, 64612870, or 64618545 on human chromosome 18; at position 59475942, 59483891, 59484573, 59484850, 59485000, 59485642, 59488442, 59488531, 59489660, or 59492183 on human chromosome 19; at position 20218657, 20222308, 20226492, 20228734, 20232506, 20243479, 20257959, 20261725, 20272988, 20274521, 20274865, 20279236, 20282727, or 20308050 on human chromosome 21; at position 19751933, 19752848, 19756298, 19756323, 19756976, 19764380, 19767837, 19769591, 19769618, 19769950, 19771148, 19771633, 19772588, 19772956, 19772978, 19773492, 19773582, 19773965, 19774278, 19774574, 19774735, 19774818, 19775246, 19776791, or 19778477 on human chromosome
 22. 4. The method of claim 3, wherein: when the base at position 20805662 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20807307 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20812307 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20814435 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20833262 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20834778 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20835387 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20843033 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20843089 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20843172 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20845152 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20851322 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20859722 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20860139 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20866984 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20868329 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20869596 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20871652 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20873726 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20885691 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20890966 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20897686 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20897690 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20897946 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20901973 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20902168 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20910482 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20912408 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20922516 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20925487 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20925556 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20927846 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20931914 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20934009 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20935818 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20937929 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20939816 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20943571 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20945070 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20945280 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20945717 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20949204 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20949302 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20951449 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20955075 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20958577 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20959014 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20960041 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20965681 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20965980 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20966007 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20969559 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20972644 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20980229 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20984365 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20986738 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20993250 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20994909 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20997023 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20999899 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21000095 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21000981 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21004018 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21006394 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21010403 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21016114 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21022160 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21024702 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21028251 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21033244 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21035367 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21035826 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21040905 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21041170 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21044669 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21050902 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21051467 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21055398 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21062830 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21063762 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21068091 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21068874 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21069797 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21072609 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21078118 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21082461 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21082628 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21084950 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21101147 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21 106482 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21107684 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21112807 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21114874 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21120116 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21120469 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21121210 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21127511 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21131101 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21136620 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21137181 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21140439 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21140663 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21141522 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21141902 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21142192 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21145524 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21149959 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54531998 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54548927 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54551090 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54552517 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54556623 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54557621 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54561302 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54561394 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54562638 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54563585 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 54563831 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 96911594 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 96938696 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 96961817 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 97005044 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 97141267 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 97653506 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 97659904 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106818235 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106828844 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106830088 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106833215 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106891798 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106912949 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106928115 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106930964 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106937218 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106971827 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 106998017 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107004258 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107006719 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107010986 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107011275 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107011305 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107011409 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107011554 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107011627 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107012941 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107014445 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107017707 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107021830 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107024684 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107025142 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107033827 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107034845 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107044596 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107047341 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107048343 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107052637 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107054139 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107056341 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107079348 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107080550 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107081508 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107086826 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107088101 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107091984 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107092704 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107093768 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107095587 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107096669 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107098220 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107100885 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107103052 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107112872 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107115313 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 107115334 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114947052 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114968711 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114969563 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114978348 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 14981253 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114984296 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115004020 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115071842 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115073938 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115075249 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115077252 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115081154 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115084567 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115087972 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115091656 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115100040 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15101751 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115103811 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115104443 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1151 1 1982 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115116141 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1151 19103 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115125087 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115127174 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115132157 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115132560 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115132947 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115139005 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15139260 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115141772 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115159909 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115167322 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115171216 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115179531 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15180386 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115182953 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115183282 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115185601 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115193640 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115200356 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115202960 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115209101 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115217819 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115226640 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115234779 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115236258 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115242333 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15242502 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115242740 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115244057 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115261728 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115268188 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115277042 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115278233 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15278345 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115278448 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115278686 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115279927 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115280070 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115281663 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115282510 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15282884 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115284407 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115285912 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115287160 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115287345 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115289952 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115292582 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115298443 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115298798 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 15303040 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 142933600 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 142994415 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 142996870 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 143024965 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 143037007 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 143039966 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 143043494 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20250764 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20250981 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20252966 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20254650 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20255588 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20256013 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20257476 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20258973 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20259648 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20260227 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49157212 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49163446 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49169518 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49180455 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49183068 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49184463 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49185265 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49186995 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49187513 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49187893 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49189694 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49190619 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49191171 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49191484 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49192006 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49195881 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49199434 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49199611 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49199634 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49199711 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49203878 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49204013 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49204336 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49205020 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49205539 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49205989 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49227109 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49239677 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49239769 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49242500 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49242583 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49244528 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49253703 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49311997 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49319087 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49329514 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49329682 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49332061 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49332761 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 49335916 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186729521 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186748482 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186752544 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186753368 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186759677 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186771130 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186774634 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186783677 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186788675 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186795981 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186797056 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186797101 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186804008 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186822924 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186841731 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186849447 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186854278 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186854406 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186856196 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186866149 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186869233 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186870116 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186873391 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186873805 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186874321 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186876760 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186877596 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186878043 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186883056 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186887466 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186891840 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186892009 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186895423 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186897281 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186898014 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186899824 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186903194 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186905158 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186910195 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186918596 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186918660 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186933341 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186935034 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186937617 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186938372 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186938761 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186940537 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186942136 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186944471 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186945120 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186950816 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187032899 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187050892 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218767422 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218767819 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218767857 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218768482 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218770121 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218770314 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218770551 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218771180 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218773021 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218777739 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218781315 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218784326 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218786186 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218789557 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218791821 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218803037 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218814280 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218816511 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218823086 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218826240 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218830515 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218832566 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218833258 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218833506 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218833898 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218835652 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218846420 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218852394 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218852478 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218871943 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 218873288 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230822818 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230822908 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230823742 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230824051 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230824308 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230824428 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230825316 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230825613 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230825877 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230827852 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230828862 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230829298 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230830081 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230830316 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230830886 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230832540 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230838320 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 230842525 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25052936 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25054402 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25056885 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25061156 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25068060 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25076452 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25084253 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25084806 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25086476 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25090198 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25090417 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25091862 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25093457 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25099388 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25100369 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25102693 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25105990 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25108277 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25112900 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25114656 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25115540 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25117575 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25118394 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25121605 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25169305 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25170688 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25184366 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25188663 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25194200 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25205423 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25207827 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 2521 1158 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25211837 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25235457 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25238040 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25239011 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25239845 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25243914 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25244932 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25245547 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25250478 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25264520 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25265009 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25269521 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25273091 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25273425 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25274083 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25275052 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25277488 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25279386 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25280012 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25280571 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25283486 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25283965 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25284812 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25285067 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25287098 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25287161 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25288171 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25291318 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25291410 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25295964 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 25300483 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62937809 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62941462 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62943033 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62943151 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62943547 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62945427 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62949979 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62955440 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62957942 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62958060 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62959133 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62959399 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62960430 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62961266 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62962215 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62964393 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62965607 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62966446 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62966549 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62968123 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62968779 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62968976 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62969677 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62970029 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62970190 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62970589 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62971291 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62972138 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62975188 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62981633 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62982901 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62983787 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 62985367 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120013362 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120013382 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120036240 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120037273 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120037336 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120037804 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120039183 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120039851 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 120044441 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186008653 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186008673 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186008910 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186012692 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186027445 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186032241 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186038166 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186041770 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186043671 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186049741 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186052729 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186056257 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186058136 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186058533 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186059022 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186060619 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186063619 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186070576 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186070838 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186072802 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186073295 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186076934 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186079782 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186081364 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186083378 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186090182 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186099834 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186104572 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186112996 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186113805 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186115949 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186117351 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186119962 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186126928 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186131728 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186142625 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186146360 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186148006 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186149057 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186152026 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186156901 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186244971 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186252104 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 186267820 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187843111 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187857373 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187860431 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 187878274 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4846426 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4857130 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4857759 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4867970 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73187634 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73200067 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73328055 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73346262 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73346848 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73348223 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73357454 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73363372 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73365920 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73368604 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73376981 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73386336 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73387894 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73401936 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73402263 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73403367 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73409745 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73418036 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73419931 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73420592 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73420874 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73420904 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73420954 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73421198 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73421361 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73421626 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73421636 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73424191 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73426574 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73428206 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73428609 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73429022 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73429166 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73429961 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73430864 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73432371 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73432662 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73433172 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73435810 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73435851 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73437550 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73437882 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73438096 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73440758 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73441001 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73441029 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73442206 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73445194 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73446950 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73448534 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73451047 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73453617 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73454336 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73455010 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73456969 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73461427 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73468266 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73468802 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73469693 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73472897 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73473510 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73474331 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73475459 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73476824 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73481968 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73482388 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73484550 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73489468 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73491229 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73491598 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73492707 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73493192 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73493907 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73496343 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73496916 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73501955 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156007562 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156008015 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156009501 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156019936 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156020341 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156027459 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156029231 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156030563 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156032538 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 156033905 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 14716570 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114718052 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114719100 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114719186 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114721020 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114724952 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114727927 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114728598 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 14729688 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114730035 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114730402 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114731087 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114734391 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114735264 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 14735588 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114735981 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114736503 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114737036 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114737354 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114739954 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114741070 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114742706 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114743558 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114743576 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114744950 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1 14747047 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114747337 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 114747490 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128103463 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128108152 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128113997 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128120050 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128134369 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128135572 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128139763 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128141175 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128146786 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128156553 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128157693 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128160641 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128164258 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128170372 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128197696 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128206257 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128220969 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128223084 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128227979 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128228401 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128232311 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128232320 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128233576 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128233727 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128234493 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128234617 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128234806 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128235438 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128235745 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128235767 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128236078 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128236528 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128238639 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128240119 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128241301 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128258653 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128260778 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128260800 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128263313 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128265259 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128269933 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128271956 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128273703 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128279649 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128280539 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128287628 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128289750 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128316551 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128327389 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128340511 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128341528 on human chromosome 5 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128345166 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128346380 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128348967 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128351543 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128352581 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128352924 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128353107 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128355391 on human chromosome 5 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128355483 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128356081 on human chromosome 5 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128358774 on human chromosome 5 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1026731 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1032864 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1033885 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1033964 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1034131 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1034217 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1035056 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1035451 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1037138 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 1037761 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69363616 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69379328 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69411039 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69414352 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69414862 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69416925 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69428738 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69429357 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69429728 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69435338 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69435377 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69435704 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69436412 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69437088 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69437132 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69437929 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69439747 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69440936 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69445347 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69447873 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69449271 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69454318 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69455343 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69461590 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69462851 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69463179 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69469800 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69471343 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69483117 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69483590 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69486083 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69490498 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69496298 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69497479 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69504298 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69504487 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69511710 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69513299 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69517615 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 69518419 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 82950808 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83037702 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83052756 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83052893 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83059529 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83059811 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83063355 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83065585 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83065715 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83066965 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83067321 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83079412 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83086171 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83086772 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83087733 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83088471 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83089659 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83092525 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83092537 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83094274 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83094499 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83094576 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83095347 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83095565 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83095939 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83096974 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83097004 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83097222 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83098262 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83098329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83098352 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83100260 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83101000 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83103870 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83104741 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83105428 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83113039 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83114887 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83120523 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83122607 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83126442 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83127291 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83129590 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83131084 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83137358 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83140060 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83146661 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83147795 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83150543 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83153296 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83155501 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83162032 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83163350 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83165082 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83165771 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83167427 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83167802 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83168404 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83169297 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83169493 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at. position 83170215 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83170490 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83170598 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83172329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 129960436 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 129962477 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 129970245 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 81554149 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 81559478 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 81641687 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 81648931 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 81654315 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144628286 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144628318 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144628632 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144629754 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144629965 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144630098 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144635813 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144643683 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144645286 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144646697 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144669590 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144669600 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144671926 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144672558 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144674138 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144676045 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144676393 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144678594 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144678612 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144680315 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144718311 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144720727 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144733732 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144733992 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144734180 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144734239 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144734742 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144738529 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144744457 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144745645 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144745774 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144745875 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144751586 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144752182 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144752705 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144753415 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144753565 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144754173 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144755233 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144755604 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144755775 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144756961 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144757255 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144759437 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144760563 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144761726 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144766026 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144766794 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144768118 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144768579 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144768715 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144770877 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144770905 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144771574 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144771653 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144771867 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144774486 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144774883 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144776678 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144777538 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144778707 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144781332 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144781771 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144782495 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144783026 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144783666 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144784599 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144785299 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144788902 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144791211 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144793063 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144796105 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144799583 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144799675 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144800213 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144800438 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144800519 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144800830 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144801300 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144802085 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144802576 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144803188 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144803650 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144804012 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144804167 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144805193 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144805467 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144806025 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144806327 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144806354 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144808010 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144810732 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144814121 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144814527 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144818301 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 144819907 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149201414 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149210939 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149213761 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149214960 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149219765 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149242664 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 149243724 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4252805 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4257185 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9426711 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9431741 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9436057 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9436101 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9436786 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9437029 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9437099 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9439838 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9440072 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9444872 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9452052 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9458679 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9460336 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9463104 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9468129 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9480306 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9503674 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9523873 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9526021 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9526193 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9529470 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9531111 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9538857 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9541393 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9546289 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9549119 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9558649 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9563755 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9568067 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9568084 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9568712 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9640154 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9645506 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9673180 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55688038 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55688723 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55688788 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55689106 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55691506 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55692165 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55698923 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55699691 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55704003 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55704066 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55704170 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55714151 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55718398 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55720864 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55724371 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55724624 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55725409 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55729655 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55732233 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55734727 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55734972 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55735628 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55735791 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55736905 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55738068 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55740834 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55741606 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55742554 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55747804 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55748460 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55752508 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55760756 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55761309 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55776456 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55783865 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55801936 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55811566 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55819136 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55821626 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55823685 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55825618 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55845129 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55858095 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55861650 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55870126 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55880446 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55883850 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 55886453 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128476372 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128476625 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128477246 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128477298 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128478414 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128478693 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128481192 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128482329 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128482487 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128483680 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128484074 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128486686 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128489299 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128490967 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128492309 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128492523 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128492580 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128492832 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128492999 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128493974 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128495575 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128500876 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128509349 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128512569 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 128524876 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138448609 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138448978 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138450507 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138450935 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138451287 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138452272 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138452507 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138452835 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138453471 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138454113 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138454197 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138454235 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138454833 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138455486 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138455728 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138456184 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138456296 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138456395 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138457265 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138458205 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138458287 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138458607 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138459228 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138459736 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138460258 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138460320 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138460491 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138461455 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138461471 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138461926 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138462319 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138467267 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138467277 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138467539 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138469853 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138469883 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138472916 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138473941 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138477490 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138481482 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138482393 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138490184 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138498734 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138545196 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138546484 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138551497 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138576626 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138578139 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138580074 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138583352 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138585809 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138585968 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138586498 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138588282 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138590203 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138590751 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138594903 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138598108 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138601596 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138601771 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138603600 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138603658 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138603708 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138604408 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138604979 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138607006 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138607169 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138607178 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138608732 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138610100 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138610110 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138610517 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138611185 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138611655 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138611699 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138611757 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138612308 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138614096 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138614490 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138614687 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138615037 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138615093 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138615852 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138616621 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138616711 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 138616778 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141567935 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141583366 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141589763 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141595220 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141595413 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141596167 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141596488 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 141597272 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6282602 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6291578 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6299862 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6300908 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6314376 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6316825 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6321421 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6321610 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6322901 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6325760 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6332328 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6340235 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6341111 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6341834 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6342819 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6349144 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6352365 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6354449 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6354533 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6355614 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6375637 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6385247 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6385540 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6386245 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6390030 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6392856 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6397799 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6397843 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6398247 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 6399874 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73606988 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73607164 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73607569 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73612124 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73613027 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73614943 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73615076 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73615232 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73616781 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73617303 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73618675 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73619146 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73622095 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73622395 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73622439 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73625852 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73626601 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73626706 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73627824 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73628740 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73629704 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73633747 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73634385 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73635467 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73635691 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73635782 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73636447 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73636612 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73636831 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73638980 on human chromosome 9 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73639771 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73639895 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73640222 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73642315 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73643177 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 79353924 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 79356465 on human chromosome 9 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 79356737 on human chromosome 9 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 79359981 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 110130428 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4430296 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4430392 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4430569 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4434860 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4440254 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4442501 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4443277 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4443753 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4444427 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4444806 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4446686 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4448408 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4449042 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4449105 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4449910 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4450407 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4450528 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4451604 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4453189 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4453492 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4453537 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4453673 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4454017 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4454894 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4532655 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 4543829 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5766124 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5766322 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5768065 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5772861 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5774897 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5775192 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5776193 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5778275 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5779169 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5779183 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5779725 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 511911 A on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5779871 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5780048 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5780227 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5781044 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5781459 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5781526 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5781557 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5781753 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5782739 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5783829 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5783893 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5784028 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5784528 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5785595 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5786072 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5792979 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5799485 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5800361 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5802527 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5802898 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43124098 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43145953 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43149399 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43151108 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43153254 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43154329 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43154718 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43155303 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43156052 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43156514 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43156937 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43158142 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43158508 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43159402 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43159607 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43160243 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43160762 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43160895 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43160975 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43161066 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43161471 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43161777 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43161927 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43167395 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43167433 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43169005 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43169462 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43170570 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 43171231 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73953815 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73956355 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73968600 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73978840 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73982157 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73987190 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73990610 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 73995062 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74002571 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74002983 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74007856 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74008628 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74009527 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74009910 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74013473 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74016841 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74017225 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74017844 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74018984 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74023198 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74024581 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74029849 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74033737 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74034353 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74036330 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74036714 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74037177 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74037678 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74039262 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74040179 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74040814 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74042214 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74042378 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74052598 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74055648 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74056519 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74058677 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74062794 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74063339 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74064448 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74067075 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74067429 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74067969 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 74071586 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83325571 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83326348 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83331489 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83333982 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83338726 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83346857 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83359180 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83378990 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83383578 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83385447 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83386501 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83387013 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83389630 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83389983 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83390829 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83400665 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83402660 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83403491 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83403720 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83404929 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83418135 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83420693 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83430317 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83504794 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83508907 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83513418 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83523059 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83525615 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83527163 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83532440 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83540697 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83542042 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83548041 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83555723 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83569470 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83570172 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83572107 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83574800 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83576676 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83594342 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83597820 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83598063 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83599752 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 83601427 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115737050 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115739067 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115741985 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115742227 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115742992 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115743244 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115744952 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115745463 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 115747903 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9803997 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9805272 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9807907 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9808088 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9808349 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9809369 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9811239 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9814096 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9814380 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9816179 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9817025 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9817331 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9817664 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9817891 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9818051 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9818837 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 9820946 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31132974 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31136113 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31144153 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31148962 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31149995 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31 152638 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31152965 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31156037 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31157580 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21846344 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21860220 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21868669 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21868693 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21870958 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 21873258 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 32643593 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 32647970 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 32655052 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 32658737 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 32665137 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45412663 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45413606 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45414960 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45416097 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45418874 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45438294 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45440577 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45445023 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45448444 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45459812 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45464824 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45484610 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45512651 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45514463 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45525440 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45538603 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45539148 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45539467 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45539686 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45540157 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45540993 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45541374 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45541562 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45542131 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45542153 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45543741 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45544445 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45546095 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45547399 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45547569 on human chromosome 13 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45548220 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45549081 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45549309 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45550691 on human chromosome 13 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45553450 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45568003 on human chromosome 13 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 45572910 on human chromosome 13 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67170429 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67184920 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67187885 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67188117 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67194680 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67197723 on human chromosome 14 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67219687 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67233546 on human chromosome 14 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67239521 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67241643 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67257453 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67258104 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67258676 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67266474 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 67276155 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46089356 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46101819 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46103228 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46108382 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46111620 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46114468 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46114858 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46116200 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 461 16311 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46116717 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 461 18326 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46118529 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46118841 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46120302 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46126798 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46136739 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46139544 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46145643 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 46149357 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93195638 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93202040 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93217814 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93221398 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93222123 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93226669 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93229804 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93231817 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93232312 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93238457 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93261273 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93263139 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93264699 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93265029 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93266435 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93266453 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93267466 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93274496 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93277598 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 93279847 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99768367 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99768456 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99768718 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99769785 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99772560 on human chromosome 15 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99772834 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99773041 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99773242 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99775105 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99775156 on human chromosome 15 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99775985 on human chromosome 15 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 99785607 on human chromosome 15 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5806139 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5806149 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5806269 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5806460 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5807386 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5807689 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5808267 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5808466 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5808524 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5808701 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5808730 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5809618 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5810450 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5812560 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5813426 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5819886 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 5828787 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23566477 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23573679 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23574058 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23576069 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23578098 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23579493 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23584507 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23584612 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23588666 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23599906 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23601271 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23602233 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23605180 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23605958 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23609039 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23611506 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23619684 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23619949 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 23620229 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 13112831 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 13114370 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 13117081 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 13117504 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 13117537 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30912424 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30918963 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30926748 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30962717 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30967908 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30967921 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30968168 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 30998594 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31001651 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31006594 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31011147 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31013421 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31023017 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31023480 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31024741 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31044721 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 31050583 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 34294350 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 34294807 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 34297013 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64574312 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64575303 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64575455 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64577169 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64577779 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64578874 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64579596 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64580779 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64584139 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64586668 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64588166 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64588368 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64589299 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64591510 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64592428 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64592919 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64593139 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64595151 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64595371 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64596256 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64596392 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64596771 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64600350 on human chromosome 18 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64601827 on human chromosome 18 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64602989 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64612870 on human chromosome 18 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 64618545 on human chromosome 18 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59475942 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59483891 on human chromosome 19 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59484573 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59484850 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59485000 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59488442 on human chromosome 19 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59488531 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59489660 on human chromosome 19 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 59492183 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20218657 on human chromosome 21 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20222308 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20226492 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20228734 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20232506 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20243479 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20257959 on human chromosome 21 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20261725 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20274521 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20274865 on human chromosome 21 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20279236 on human chromosome 21 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20282727 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 20308050 on human chromosome 21 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19751933 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19752848 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19756298 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19756323 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19756976 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19764380 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19767837 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19769591 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19769618 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19769950 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19771148 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19771633 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19772588 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19772956 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19772978 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19773492 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19773965 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19774278 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19774574 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19774735 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19774818 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19775246 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19776791 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk; when the base at position 19778477 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk.
 5. The method of claim 4, wherein the base is selected from one of those specifically enumerated in claim
 3. 6. The method of claim 5, wherein the allelic effect is as specified in any of Tables 1 to 85, as it applies to the specified base. 7-33. (canceled) 